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WO2018052838A1 - Fungicidal pyrazoles - Google Patents

Fungicidal pyrazoles Download PDF

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Publication number
WO2018052838A1
WO2018052838A1 PCT/US2017/050919 US2017050919W WO2018052838A1 WO 2018052838 A1 WO2018052838 A1 WO 2018052838A1 US 2017050919 W US2017050919 W US 2017050919W WO 2018052838 A1 WO2018052838 A1 WO 2018052838A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
formula
fungicides
compounds
Prior art date
Application number
PCT/US2017/050919
Other languages
French (fr)
Inventor
Andrew Edmund Taggi
James Francis Bereznak
Yuzhong Chen
Jeffrey Keith Long
Travis Chandler MCMAHON
Original Assignee
E. I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E. I. Du Pont De Nemours And Company filed Critical E. I. Du Pont De Nemours And Company
Publication of WO2018052838A1 publication Critical patent/WO2018052838A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to certain pyrazoles, their N-oxides, salts and compositions, and methods of their use as fungicides.
  • This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides:
  • R 1 is halogen
  • R 2 is H or halogen
  • R 3 is halogen
  • R 4 is H or halogen
  • X is NR 5 or CR 6 OR 7 ;
  • R 6 is H or C 1 -C 6 alkyl
  • R 8 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl
  • R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 3 -C 6
  • ach R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl;
  • R 12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 3 -C 6
  • each R13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl;
  • W is O or S
  • M + is K, Na or Li
  • n 0, 1 or 2.
  • this invention pertains to a compound selected from compounds of Formula 1 (including all stereoisomers) and N-oxides and salts thereof.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • This invention also relates to a fungicidal composition
  • a fungicidal composition comprising (a) a compound of the invention; and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
  • This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein).
  • a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one invertebrate pest control compound or agent.
  • compositions As used herein, the terms“comprises,”“comprising,”“includes,”“including,”“has,” “having,”“contains,”“containing,”“characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
  • transitional phrase“consisting essentially of” is used to define a composition, method or apparatus that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • the term“consisting essentially of” occupies a middle ground between “comprising” and“consisting of”.
  • “or” refers to an inclusive or and not to an exclusive or.
  • a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • indefinite articles“a” and“an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore“a” or“an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
  • “plant” includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds).
  • Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
  • seedling means a young plant developing from the embryo of a seed.
  • the term“broadleaf” used either alone or in words such as “broadleaf crop” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
  • alkylating agent refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to a leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom.
  • a leaving group such as halide or sulfonate
  • the term“alkylating agent” or“alkylating reagent” does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified, for example, for R 5 .
  • a molecular fragment i.e. radical
  • a series of atom symbols e.g., C, H, N, O, S
  • the point or points of attachment may be explicitly indicated by a hyphen (“-”).
  • alkyl used either alone or in compound words such as“alkylthio” or“haloalkyl” includes straight-chain or branched alkyl such as methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.“Alkynyl” includes straight-chain or branched alkynes such as 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkylamino includes an NH radical substituted with straight-chain or branched alkyl.
  • alkylamino include CH 3 CH 2 NH, CH 3 CH 2 CH 2 NH and (CH 3 ) 2 CHNH.
  • dialkylamino include (CH 3 ) 2 N, (CH 3 CH 2 ) 2 N and CH 3 CH 2 (CH 3 )N.
  • Alkylaminoalkyl denotes alkylamino substitution on alkyl.
  • alkylaminoalkyl include CH 3 NHCH 2 , CH 3 NHCH 2 CH 2 and CH 3 CH 2 NHCH 2 .
  • dialkylaminoalkyl examples include (CH 3 ) 2 NCH 2 , CH 3 CH 2 (CH 3 )NCH 2 and (CH 3 ) 2 NCH 2 CH 2 .
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, i-propyloxy and the different butoxy, pentoxy and hexyloxy isomers.“Alkoxyalkyl” denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Alkenyloxy includes straight-chain or branched alkenyl attached to and linked through an oxygen atom.
  • alkynyloxy includes straight-chain or branched alkynyl attached to and linked through an oxygen atom. Examples of “alkynyloxy” include HC ⁇ CCH 2 O, CH 3 C ⁇ CCH 2 O and CH 3 C ⁇ CCH 2 CH 2 O.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • cycloalkyl denotes a saturated carbocyclic ring consisting of between 3 to 7 carbon atoms linked to one another by single bonds.
  • examples of“cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the term“cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl group.
  • Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • halogen either alone or in compound words such as“halomethyl”, “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as“haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, ClCH 2 , CF 3 CH 2 and CF 3 CCl 2 .
  • haloalkoxy is defined analogously to the term “haloalkyl”. Examples of “haloalkoxy” include CF 3 O, CCl 3 CH 2 O, F 2 CHCH 2 CH 2 O and CF 3 CH 2 O.
  • T he total number of carbon atoms in a substituent group is indicated by the“C i -C j ” prefix where i and j are numbers from 1 to 8.
  • C 1 -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl
  • C 2 alkoxyalkyl designates CH 3 OCH 2
  • C 3 alkoxyalkyl designates, for example, CH 3 OCH 2 CH 2 or CH 3 CH 2 OCH 2
  • C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • the term“unsubstituted” in connection with a group such as a ring means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1.
  • the term“optionally substituted” means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) range from 1 to 3.
  • the term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term“(un)substituted.”
  • the number of optional substituents may be restricted by an expressed limitation.
  • the phrase“optionally substituted with up to 2 substituents independently selected from R 11 ” means that 0, 1 or 2 substituents can be present (if the number of potential connection points allows).
  • “carbocyclic ring” or“carbocycle” denote a ring wherein the atoms forming the ring backbone are selected only from carbon. When a fully unsaturated carbocyclic ring satisfies Hückel’s rule, then said ring is also called an“aromatic carbocyclic ring”.
  • saturated carbocyclic ring refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
  • Compounds of this invention can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
  • salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms.
  • the salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • Formula 1 includes all crystalline and non- crystalline forms of the compounds that Formula 1 represents.
  • Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts.
  • Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types).
  • polymorph refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice.
  • polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability.
  • a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1.
  • Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
  • Embodiments of the present invention as described in the Summary of the Invention include those described below.
  • Formula 1 includes stereoisomers, N-oxides and salts thereof, and reference to“a compound of Formula 1” includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
  • Embodiment 2 A compound of Embodiment 1 wherein X is NH.
  • Embodiment 4 A compound of Embodiment 3 wherein X is CHOH.
  • Embodiment 5 A compound of Formula 1 wherein X is NH or CHOH.
  • Embodiment 6 A compound of Formula 1 or any one of Embodiments 1 through 5 w herein R 1 is Br, Cl or F.
  • E mbodiment 7 A compound of Embodiment 6 wherein R 1 is Br or Cl.
  • Embodiment 8 A compound of Formula 1 or any one of Embodiments 1 through 7 w herein R 2 is halogen.
  • Embodiment 9. A compound of Embodiment 8 wherein R 2 is Br, Cl or F.
  • Embodiment 11 A compound of Formula 1 or any one of Embodiments 1 through 7 w herein R 2 is H, Br, Cl or F.
  • Embodiment 14 A compound of Formula 1 or any one of Embodiments 1 through 13 w herein R 3 is Br, Cl or F.
  • Embodiment 15 A compound of Formula 1 or any one of Embodiments 1 through 14 w herein R 4 is H.
  • Embodiment 16 A compound of Formula 1 or any one of Embodiments 1 through 14 w herein R 4 is halogen.
  • E mbodiment 17 A compound of Embodiment 16 wherein R 4 is Br, Cl or F.
  • E mbodiment 18 A compound of Embodiment 17 wherein R 4 is Cl or F.
  • Embodiment 20 A compound of Formula 1 or any one of Embodiments 1 through 14 w herein R 4 is H, Br, Cl or F.
  • Embodiment 24 A compound of Embodiment 23 wherein R 5 is H,
  • Embodiment 29 A compound of Formula 1 or any one of Embodiments 1 through 28 w herein R 6 is H or methyl.
  • Embodiment 36 A compound of Formula 1 or any one of Embodiments 1 through 35 w herein R 8 is methyl or halomethyl.
  • Embodiment 37 A compound of Formula 1 or any one of Embodiments 1 through 36 w herein R9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 a lkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
  • E mbodiment 38 A compound of Embodiment 37 wherein R9 is C 1 -C 3 alkyl, C 2 -C 4 a lkoxyalkyl, C 4 -C 6 cycloalkylalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 a lkenyloxy C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl.
  • E mbodiment 39 A compound of Embodiment 38 wherein R9 is C 1 -C 3 alkyl, C 2 -C 3 a lkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyloxy or C 1 -C 3 alkylthio.
  • E mbodiment 40 A compound of Embodiment 39 wherein R 9 is methyl, ethyl,
  • E mbodiment 41 A compound of Embodiment 40 wherein R 9 is methyl, methoxy or methylthio.
  • E mbodiment 44 A compound of Embodiment 43 wherein R 10 is cyclopropyl, methyl or ethyl.
  • Embodiment 45 A compound of Formula 1 or any one of Embodiments 1 through 44 w herein each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio.
  • Embodiment 46 A compound of Embodiment 45 wherein each R 11 is independently c yano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio.
  • Embodiment 47 A compound of Embodiment 46 wherein each R 11 is independently c yano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
  • E mbodiment 48 A compound of Embodiment 47 wherein each R 11 is independently c yano, cyclopropyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
  • E mbodiment 49 A compound of Embodiment 48 wherein each R 11 is independently cyano, cyclopropyl, methoxy or methylthio.
  • Embodiment 50 A compound of Formula 1 or any one of Embodiments 1 through 49 w herein R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 4 -C 8 c ycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 a lkylthio or C 2 -C 6 alkylthioalkyl.
  • E mbodiment 51 A compound of Embodiment 50 wherein R12 is C 1 -C 6 alkyl, C 2 -C 6 a lkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 a lkylthio or C 2 -C 6 alkylthioalkyl.
  • E mbodiment 52 A compound of Embodiment 51 wherein R12 is C 1 -C 3 alkyl, C 2 -C 4 a lkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 3 alkoxy, C 2 -C 4 alkenyloxy, C 1 -C 3 a lkylthio or C 2 -C 4 alkylthioalkyl.
  • E mbodiment 53 A compound of Embodiment 52 wherein R12 is C 1 -C 3 alkyl, C 2 -C 4 a lkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl.
  • E mbodiment 54 A compound of Embodiment 53 wherein R 12 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
  • E mbodiment 55 A compound of Embodiment 54 wherein R 12 is methyl, methoxy or methylthio.
  • Embodiment 56 A compound of Formula 1 or any one of Embodiments 1 through 55 w herein each R13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio.
  • E mbodiment 57 A compound of Embodiment 56 wherein each R 13 is independently c yano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio.
  • Embodiment 58 A compound of Embodiment 57 wherein each R 13 is independently c yano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
  • each R 13 is independently c yano, cyclopropyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
  • E mbodiment 60 A compound of Embodiment 59 wherein each R 13 is independently cyano, cyclopropyl, methoxy or methylthio.
  • Embodiment 61 A compound of Formula 1 or any one of Embodiments 1 through 60 wherein W is O.
  • Embodiment 63 A compound of Formula 1 or any one of Embodiments 1 through 62 wherein m is 0.
  • Embodiment 64 A compound of Formula 1 or any one of Embodiments 1 through 63 w herein R 1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is H; or
  • R 1 is Br or Cl
  • R 2 is F
  • R 3 is Br, Cl or F and R 4 is F; or
  • R 1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is H; or
  • R 1 is Br or Cl
  • R 2 is Cl
  • R 3 is Br, Cl or F
  • R 4 is F.
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1.
  • embodiments of this invention including Embodiments 1-64 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
  • Embodiment A A compound of Formula 1 wherein
  • R 1 is Br, Cl or F
  • R 2 is halogen
  • R 3 is Br, Cl or F
  • R 4 is H, Br, Cl or F
  • R 6 is H or methyl
  • R 8 is methyl or halomethyl
  • R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl;
  • R 12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 4 -C 8 c ycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl;
  • R 13 is cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio;
  • W is O.
  • Embodiment B A compound of Embodiment A wherein
  • R 2 is Br, Cl or F
  • R 9 is C 1 -C 3 alkyl, C 2 -C 4 alkoxyalkyl, C 4 -C 6 cycloalkylalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyloxy C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl;
  • R 11 is cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio;
  • R 12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
  • Embodiment C A compound of Embodiment B wherein
  • R 6 is H;
  • R 9 is C 1 -C 3 alkyl, C 2 -C 3 alkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy,
  • R 10 is cyclopropyl, methyl or ethyl.
  • Embodiment D A compound of Embodiment C wherein
  • R 1 is Br or Cl
  • R 2 is Cl or F
  • R 4 is H or F
  • R 9 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
  • Embodiment E A compound of Embodiment C or Formula 1 wherein X is NH;
  • R 1 is Br or Cl
  • R 2 is F
  • R 3 is Br, Cl or F and R 4 is H; or
  • R 1 is Br or Cl
  • R 2 is F
  • R 3 is Br, Cl or F and R 4 is F; or
  • R 1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is H; or
  • R 1 is Br or Cl
  • R 2 is Cl
  • R 3 is Br, Cl or F
  • R 4 is F.
  • Specific embodiments include compounds of Formula 1 selected from the group consisting of:
  • compounds of Formula 1 can be prepared by reaction of 1H-pyrazole compounds of Formula 2 with methylating agents of formula CH 3 -L 1 wherein L 1 is a leaving group such as halogen (e.g., Cl, Br, I), sulfonate (e.g., mesylate (OS(O) 2 CH 3 ), triflate (OS(O) 2 CF 3 ), or p-toluenesulfonate) or phosphate (e.g., dimethyl phosphate), preferably in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate or potassium hydroxide, and in a solvent such as N,N- dimethylformamide, tetrahydrofuran, toluene or water.
  • L 1 is a leaving group such as halogen (e.g., Cl, Br, I), sulfonate (e.g., mesylate (OS(O) 2 CH 3
  • methylating agents include diazomethane and iodomethane using general procedures known in the art, such as those described in Canada Journal of Chemistry 1986, 64, 2211-2219 and Heterocycles 2000, 53(12), 2775-2780.
  • compounds of Formula 1a can be prepared by reaction of compounds of Formula 3 with compounds of Formula 4 wherein L 2 is a leaving group such as halogen (e.g., Cl, Br, I) or sulfonate (e.g., mesylate (OS(O) 2 CH 3 ), triflate (OS(O) 2 CF 3 ) or p-toluenesulfonate), optionally in the presence of a metal catalyst, and generally in the presence of a base and a polar aprotic solvent such as N,N-dimethylformamide or dimethyl sulfoxide.
  • halogen e.g., Cl, Br, I
  • sulfonate e.g., mesylate (OS(O) 2 CH 3 ), triflate (OS(O) 2 CF 3 ) or p-toluenesulfonate
  • the use of a metal catalyst in amounts ranging from catalytic up to superstoichiometric can facilitate the desired reaction.
  • the reaction can be run in the presence of a metal catalyst such as copper salt complexes (e.g., CuI with N,N'-dimethylethylenediamine, proline or bipyridyl), palladium complexes (e.g., tris(dibenzylideneacetone)dipalladium(0)) or palladium salts (e.g., palladium acetate) with ligands such as 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl or 2,2'-bis- (diphenylphosphino)1,1'-binaphthalene, with a base such as potassium carbonate, cesium carbonate, potassium phosphate, sodium phenoxide
  • compounds of Formula 1a can be prepared by reaction of compounds of Formula 5 with compounds of Formula 6 under metal-catalyzed conditions, as described above for Scheme 2.
  • Scheme 3 See, for example, Bioorganic & Medicinal Chemistry Letters 2007, 17, 1189-1192.
  • intermediates of Formula 5 wherein L 2 is Br or I can be prepared by reaction of 5-aminopyrazoles of Formula 3a (i.e. Formula 3 wherein R 5 is H) under diazotization conditions optionally in the presence of copper salts containing bromide or iodide.
  • 5-aminopyrazoles of Formula 3a i.e. Formula 3 wherein R 5 is H
  • diazotization conditions optionally in the presence of copper salts containing bromide or iodide.
  • addition of tert-butyl nitrite to a solution of a 5-aminopyrazole of Formula 3a in the presence of CuBr 2 in a solvent such as acetonitrile provides the corresponding 5-bromopyrazole of Formula 5.
  • a 5-aminopyrazole of Formula 3a can be converted to a diazonium salt and then to a corresponding 5-bromo or 5-iodopyrazole of Formula 5 by treatment with sodium nitrite in solvents such as water, acetic acid or trifluoroacetic acid, in the presence of a mineral acid typically containing the same halide atom as L 2 (e.g., aqueous HI solution for L 2 being I), followed by treatment with the corresponding copper(I) or copper(II) salt according to general procedures well-known to those skilled in the art.
  • solvents such as water, acetic acid or trifluoroacetic acid
  • compounds of Formula 5 wherein L 2 is Br can also be prepared by reacting pyrazolones of Formula 7 with phosphorus tribromide using the method described in Tetrahedron Lett.2000, 41(24), 4713-4716.
  • Starting pyrazolones of Formula 7 can be prepared by condensation of methyl ketoesters with methyl hydrazine using the method described in Tetrahedron Lett. 2000, 41(24), 4713-4716 and J. Heterocyclic Chem. 1987, 24, 149-153.
  • compounds of Formula 5 where L 2 is fluoroalkylsulfonyl can be prepared from 5-hydroxypyrazoles of Formula 8 using the method described in Synlett 2004, (5), 795-798.
  • General methods useful for preparing starting compounds of Formula 8 are well-known in the art; for conditions see, for example, Synlett 2004, (5), 795-798 and Chemical & Pharmaceutical Bulletin 1994, 42(8), 1617-1630.
  • compounds of Formula 1 can be prepared by reaction of 4-bromo or 4-iodo pyrazoles of Formula 9 with organometallic compounds of Formula 10 under transition-metal-catalyzed cross-coupling reaction conditions, in the presence of a suitable palladium, copper or nickel catalyst.
  • compounds of Formula 10 are organoboronic acids (e.g., M 1 is B(OH) 2 ), organoboronic esters (e.g., M1 is B(-OC(CH 2 ) 3 O-), organotrifluoroborates (e.g., M1 is BF 3 K), organotin reagents (e.g., M 1 is Sn(n-Bu) 3 , Sn(Me) 3 ), Grignard reagents (e.g., M 1 is MgBr or MgCl) or organozinc reagents (e.g., M 1 is ZnBr or ZnCl).
  • organoboronic acids e.g., M 1 is B(OH) 2
  • organoboronic esters e.g., M1 is B(-OC(CH 2 ) 3 O-
  • organotrifluoroborates e.g., M1 is BF 3 K
  • organotin reagents e.g.
  • Suitable metal catalysts include, but are not limited to: palladium(II) acetate, palladium(II) chloride, tetrakis(triphenylphosphine)- palladium(0), bis(triphenylphosphine)palladium(II) dichloride, dichloro[1,1'-bis(diphenyl- phosphino)ferrocene]palladium(II), bis(triphenylphosphine)dichloronickel(II) and copper(I) salts (e.g., copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) cyanide or copper(I) triflate).
  • palladium(II) acetate palladium(II) chloride
  • tetrakis(triphenylphosphine)- palladium(0) bis(triphenylphosphine)palladium(II) dichloride, dichloro
  • Optimal conditions will depend on the catalyst used and the counterion attached to the coupling reagent (i.e. M 1 ), as is understood by one skilled in the art.
  • a ligand such as a substituted phosphine or a substituted bisphosphinoalkane promotes reactivity.
  • a base such as an alkali carbonate, tertiary amine or alkali fluoride may be necessary for some reactions involving organoboron reagents of the Formula 10.
  • a base such as an alkali carbonate, tertiary amine or alkali fluoride
  • 5-aminopyrazoles of Formulae 3 and 3a can also be prepared by reacting 4-bromo or 4-iodo pyrazoles of Formula 12 with compounds of Formula 10a (i.e. Formula 10 wherein M 1 is B(OH) 2 ) using transition-metal-catalyzed cross-coupling reaction conditions as described in the method of Scheme 7.
  • pyrazole intermediates of Formula 9 are readily prepared from corresponding pyrazoles of Formula 13 by treatment with a halogenating agent.
  • Suitable halogenating agents for this method include N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, sodium bromite, thionyl chloride, oxalyl chloride, phenylphosphonic dichloride or phosgene.
  • Suitable solvents for this reaction include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, chlorobutane, benzene, xylenes, chlorobenzene, tetrahydrofuran, p-dioxane, acetonitrile, and the like.
  • an organic base such as triethylamine, pyridine, N,N-dimethylaniline, and the like can be added.
  • Typical reaction temperatures range from about ambient temperature to 200 ⁇ C. For representative procedures see Synthesis 2006, 17, 2855-2864; Journal of Medicinal Chemistry 2005, 48, 6843-6854; Journal of Medicinal Chemistry 2007, 50, 3086-3100 and Journal of Medicinal Chemistry 2005, 48, 4420-4431.
  • intermediates of Formula 12 can be prepared from compounds of Formula 14 using reaction conditions similar to those described for Scheme 10.
  • Compounds of Formula 14 are commercially available and can be prepared by methods known in the art.
  • compounds of Formula 13 can be prepared from corresponding compounds of Formula 15 by procedures analogous to those used for the method of Scheme 2.
  • Compounds of Formula 15 are commercially available or can be prepared by methods known in the art.
  • compounds of Formula 1a i.e. Formula 1 wherein X is NR 5
  • compounds of Formula 17 are condensed with methylhydrazine in a solvent such as ethanol or methanol and optionally in the presence of an acid or base catalyst such as acetic acid, piperidine or sodium methoxide, according to general procedures known in the art.
  • an acid or base catalyst such as acetic acid, piperidine or sodium methoxide
  • Compounds of Formula 2 (shown in the method of Scheme 1) can be prepared by condensing compounds of Formula 17 with hydrazine, in a manner analogous to the method of Scheme 14. This method is described in Chemistry of Heterocyclic Compounds 2005, 41(1), 105–110.
  • compounds of Formula 17 wherein, R b is H or lower alkyl can be prepared by reacting the corresponding ketene dithioacetal compounds of Formula 18 w ith compounds of Formula 6 (wherein R 5 is H) optionally in the presence of a base, such as sodium hydride or ethylmagnesium chloride, in solvents such as toluene, tetrahydrofuran or dimethoxymethane, at temperatures ranging from about–10 °C to the boiling point of the solvent.
  • a base such as sodium hydride or ethylmagnesium chloride
  • solvents such as toluene, tetrahydrofuran or dimethoxymethane
  • compounds of Formula 17 wherein R b is lower alkyl (e.g., methyl, ethyl, n-propyl) and Formula 17a (i.e. tautomer of Formula 17 when R b is H) can be prepared via a condensation reaction of corresponding isothiocyanate compounds of Formula 20 with arylacetone compounds of Formula 21 to give intermediate compounds of Formula 22, which are salts of the thioamides of Formula 17a.
  • the intermediate compounds of Formula 22 can either be used in situ (as is illustrated in WO 2013/116251, Synthesis Example 1, Step C) or isolated before further conversion (as is illustrated in WO 2013/116251, Example 2, Step A).
  • Bases useful for preparing compounds of Formula 22 include hydrides, alkoxides, hydroxides or carbonates of sodium or potassium, such as sodium hydride, potassium tert-butoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide or potassium carbonate.
  • Amine bases e.g., triethylamine or N,N-diisopropyl- ethylamine
  • solvents such as tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide, alcohols (e.g., ethanol), esters (e.g., ethyl acetate or isopropyl acetate), or mixtures thereof.
  • Solvents are chosen for compatibility with the base selected, as is well-known in the art. Reaction temperatures can range from–78 °C to the boiling point of the solvent.
  • One useful mixture of base and solvent is potassium tert- butoxide or potassium tert- pentoxide in tetrahydrofuran, to which at–70 to 0 °C is added a solution of an isothiocyanate of Formula 20 and a carbonyl compound of Formula 21, which are either combined into one solution, or added separately, preferably by addition of the carbonyl compound followed by addition of the isothiocyanate.
  • the salt compound of Formula 22 can be acidified to form the ketothioamide compound of Formula 17a or alkylated with R b X 1 (Formula 23) wherein R b is lower alkyl (e.g., methyl, ethyl, n-propyl) and X1 is a nucleofuge (i.e. a nucleophilic reaction leaving group such as Br, I, OS(O) 2 CH 3 ) to form the corresponding compound of Formula 17.
  • R b is lower alkyl (e.g., methyl, ethyl, n-propyl)
  • X1 is a nucleofuge (i.e. a nucleophilic reaction leaving group such as Br, I, OS(O) 2 CH 3 ) to form the corresponding compound of Formula 17.
  • This general method is known in the chemical literature; see, for example, Zhurnal Organicheskoi Khimii 1982, 18(12), 2501.
  • Ketothioamides of Formula 17a can also be prepared by allowing the corresponding ketoamides to react with sulfurizing agents such as Lawesson’s reagent or P 2 S 5 ; see, for example, Helv. Chim. Act.1998, 81(7), 1207.
  • sulfurizing agents such as Lawesson’s reagent or P 2 S 5 ; see, for example, Helv. Chim. Act.1998, 81(7), 1207.
  • compounds of Formula 1 and their intermediates described herein can be subjected to various electrophilic, nucleophilic, organometallic, oxidation and reduction reactions to add substituents or modify existing substituents, and thus provide other functionalized compounds of Formula 1.
  • compounds of Formula 1 can be prepared by the reaction of the compounds of Formula 24 wherein L 2 leaving group such as a halogen (e.g., Br, I) or sulfonate (e.g., mesylate, triflate, p-toluenesulfonate) with reagents such as 2,4,6-trimethylboroxine, tetramethylstannane or potassium trifluromethyl- borate in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]- palladium(II) chloride dichloromethane adduct, preferably in the presence of a base such as 1,8-diazabicyclo[5.4.0]
  • L 2 leaving group such
  • This reaction can be carried out in excess alkylating agent (e.g., iodomethane) or using a variety of solvents such as ethers, acetonitrile or N,N-dimethylformamide.
  • alkylating agent e.g., iodomethane
  • solvents such as ethers, acetonitrile or N,N-dimethylformamide.
  • Compounds of Formula 24 can be prepared by methods described in PCT Patent Publications WO 2010/101973 and WO 2012/031061.
  • S cheme 18 illustrates another example where compounds of Formula 1a wherein R 5 is other than H can be prepared from the corresponding compounds of Formula 1a wherein R 5 is H by reaction with an electrophile comprising R 5 (i.e. Formula 25).
  • an electrophile comprising R 5 i.e. Formula 25
  • the reaction is done in the presence of a base such as sodium hydride and a polar solvent such as N,N- dimethylformamide.
  • electrophile comprising R 5 means a chemical compound capable of transferring an R 5 moiety to a nucleophile (such as the nitrogen atom in Formula 1a when R 5 is H).
  • electrophiles comprising R 5 have the formula R 5 X 1 wherein X 1 is a nucleofuge (i.e.
  • nucleofuges include halide (e.g., Br, Cl, I) or sulfonate (e.g., mesylate, triflate, p- toluenesulfonate).
  • electrophiles comprising R 5 do not comprise a nucleofuge; an example is sulfur trioxide (SO 3 ), which after deprotonation (such as by a base of the formulae M + H – wherein M + is a cation) of the nitrogen atom in Formula 1a, can bond to the nitrogen atom as a -SO 3 M substituent.
  • SO 3 sulfur trioxide
  • C ompounds of Formula 1b (i.e. Formula 1 where in X is CR 6 OR 7 ) wherein R 6 and R 7 are H can be prepared as shown in Scheme 19.
  • organometallic reagents of Formula 27 such as alkyl lithium base (e.g., n-butyllithium, s-butyllithium or lithium diisopropylamide) or Grignard reagents in a solvent such as toluene, diethyl ether, tetrahydrofuran or dimethoxymethane at temperatures ranging from about–78 °C to ambient temperature.
  • the resulting anions are then contacted with aldehydes of Formula 28 to provide compounds Formula 1b.
  • Aldehydes of Formula 28 are commercially available and can be prepared by methods known in the art.
  • Compounds of Formula 26 are known and can be prepared by methods analogous to those disclosed in Schemes 4 and 5, and by a variety of methods disclosed in the chemical literature.
  • compounds of Formula 1b wherein R 6 is alkyl can be prepared by reacting compounds of Formula 29 with alkylmagnesium halide. Typically the reaction is run in the presence of zinc chloride and in a solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from about 0 to 100 °C (for references see, for example, Organic Lett.2009, 11, 1659-1662 and J. Am. Chem. Soc.2006, 128, 9998-9999).
  • compounds of Formula 29 can be prepared by contacting compounds of Formula 30 with acid chlorides of Formula 31 in the presence of a Lewis acid (e.g., aluminum chloride, boron trifluoride diethyl etherate or tin tetrachloride) in a solvent such as dichloromethane, tetrachloroethane or nitrobenzene, at temperatures ranging from about 0 to 200 °C.
  • a Lewis acid e.g., aluminum chloride, boron trifluoride diethyl etherate or tin tetrachloride
  • a solvent such as dichloromethane, tetrachloroethane or nitrobenzene
  • the reaction mixture was stirred for 3 h while maintaining the temperature at about 0 to 5 °C, after which time isopropenyl acetate (20.0 g, 200 mmol) was added, followed by a solution of copper(II) sulfate pentahydrate (0.34 g, 1.4 mmol) in water (5 mL). After stirring for 5 minutes, a solution of sodium sulfite (1.6 g) in water (40 mL) was added to the reaction mixture while maintaining the reaction temperature between about 10 to 20 °C. The reaction mixture was allowed to warm to room temperature and stirred for about 24 h. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with saturated aqueous ammonium chloride.
  • Step B Preparation of ⁇ -acetyl-N-(2-bromo-6-fluoro-4-methylphenyl)-2-chloro-4- cyanobenzeneethanethioamide (tautomer of 4-[1-[[(2-bromo-6-fluoro-4- methylphenyl)amino]mercaptomethylene]-2-oxoproply]-3-chlorobenzonitrile) Potassium tert-pentoxide (1.7 M in toluene, 1.57 mL, 2.58 mmol) was added to a solution of tetrahydrofuran (12 mL).
  • the reaction mixture was cooled to about–10 °C, and then a mixture of 3-chloro-4-(2-oxopropyl)benzonitrile (i.e. the product of Step A) (0.50 g, 2.58 mmol) and 1-bromo-3-fluoro-2-isothiocyanato-5-methylbenzene (0.58 g, 2.35 mmol) in toluene (5 mL) was added dropwise while maintaining the reaction temperature below 5 °C. The reaction mixture was stirred for 10 minutes at about–10 °C, and then hydrochloric acid (1 N aqueous solution, 2.94 mL) was added dropwise while maintaining the temperature below 5 °C.
  • Step C Preparation of 4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl- 1H-pyrazol-4-yl]-3-chlorobenzonitrile
  • the layers were separated and the aqueous phase was extracted with ethyl acetate.
  • the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • the resulting material was purified by medium pressure liquid chromatography through silica gel (eluting with a gradient of ethyl acetate/hexanes 0:100 to 40:60).
  • the resulting material was triturated in a mixture of ethyl acetate, hexanes and n-butyl chloride to provide the title, a compound of the present invention, as a solid (0.25 g).
  • compounds of Formula 22 are salts of the thioamides of Formula 17a.
  • Illustrative of compounds of Formula 22 are those specifically disclosed in Table 2 below.
  • compounds of Formula 6 are useful process intermediates for preparing compounds of Formula 1. Additionally, compounds of Formula 6 (when R 5 is H) are useful process intermediates for preparing compounds of Formula 17 (as shown in Scheme 15), which in turn are useful intermediates for preparing compounds of Formula 1.
  • An example of a compound of Formula 6 (when R 5 is H) is specifically disclosed in Step A of Example 1. Additional examples are found in Table 4 below.
  • a compound of this invention will generally be used as a fungicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serve as a carrier.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
  • Useful formulations include both liquid and solid compositions.
  • Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels.
  • aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion.
  • nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
  • the general types of solid compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible (“wettable”) or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or “overcoated”). Encapsulation can control or delay release of the active ingredient.
  • An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
  • Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
  • the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
  • Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N- dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N- methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy- 4-methyl-2-pentan
  • Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C 6 -C 22 ), such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof.
  • plant seed and fruit oils e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel
  • animal-sourced fats e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil
  • Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation.
  • alkylated fatty acids e.g., methylated, ethylated, butylated
  • Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
  • the solid and liquid compositions of the present invention often include one or more surfactants.
  • surfactants also known as“surface-active agents”
  • surface-active agents generally modify, most often reduce, the surface tension of the liquid.
  • surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
  • Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene
  • Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of e
  • Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
  • amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amine
  • Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon’s Emulsifiers and Detergents, annual American and International Editions published by McCutcheon’s Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
  • compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants).
  • formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes.
  • Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes.
  • formulation auxiliaries and additives include those listed in McCutcheon’s Volume 2: Functional Materials, annual International and North American editions published by McCutcheon’s Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
  • the compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent.
  • Solutions, including emulsifiable concentrates can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water.
  • Active ingredient slurries, with particle diameters of up to 2,000 ⁇ m can be wet milled using media mills to obtain particles with average diameters below 3 ⁇ m.
  • Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 ⁇ m range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques.
  • Pellets can be prepared as described in U.S.4,172,714.
  • Water- dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493.
  • Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030.
  • Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
  • Compound 5 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
  • Compound 8 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No.25–50 sieves)
  • Compound 9 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
  • Compound 11 10.0% polyoxyethylene sorbitol hexoleate 20.0% C 6 –C 10 fatty acid methyl ester 70.0%
  • Compound 6 20.00% polyvinylpyrrolidone-vinyl acetate copolymer 5.00% montan acid wax 5.00% calcium ligninsulfonate 1.00% polyoxyethylene/polyoxypropylene block copolymers 1.00% stearyl alcohol (POE 20) 2.00% polyorganosilane 0.20% colorant red dye 0.05% water 65.75%
  • Water-soluble and water-dispersible formulations are typically diluted with water to form aqueous compositions before application.
  • Aqueous compositions for direct applications to the plant or portion thereof typically contain at least about 1 ppm or more (e.g., from 1 ppm to 100 ppm) of the compound(s) of this invention.
  • the compounds of this invention are useful as plant disease control agents.
  • the present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound.
  • the compounds and/or compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, turf, vegetable, field, cereal, and fruit crops.
  • pathogens include: Oomycetes, including Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora capsici, Pythium diseases such as Pythium aphanidermatum, and diseases in the Peronosporaceae family such as Plasmopara viticola, Peronospora spp. (including Peronospora tabacina and Peronospora parasitica), Pseudoperonospora spp.
  • Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora capsici
  • Pythium diseases such as Pythium aphanidermatum
  • diseases in the Peronosporaceae family such as
  • Botrytis diseases such as Botrytis cinerea, Monilinia fructicola, Sclerotinia diseases such as Sclerotinia sclerotiorum, Sclerotinia minor, Magnaporthe grisea, and Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis and Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp.
  • Puccinia spp. such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis
  • Rutstroemia floccosum also known as Sclerotinia homoeocarpa
  • Rhizoctonia solani Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporumVerticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticola; Rhizopus spp. (such as Rhizopus stolonifer); Aspergillus spp. (such as Aspergillus flavus and Aspergillus parasiticus); and other genera and species closely related to these pathogens.
  • compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species.
  • the compounds of this invention are useful in treating postharvest diseases of fruits and vegetables caused by fungi and bacteria. These infections can occur before, during and after harvest. For example, infections can occur before harvest and then remain dormant until some point during ripening (e.g., host begins tissue changes in such a way that infection can progress); also infections can arise from surface wounds created by mechanical or insect injury. In this respect, the compounds of this invention can reduce losses (i.e.
  • Treatment of postharvest diseases with compounds of the invention can increase the period of time during which perishable edible plant parts (e.g, fruits, seeds, foliage, stems, bulbs, tubers) can be stored refrigerated or un-refrigerated after harvest, and remain edible and free from noticeable or harmful degradation or contamination by fungi or other microorganisms.
  • Treatment of edible plant parts before or after harvest with compounds of the invention can also decrease the formation of toxic metabolites of fungi or other microorganisms, for example, mycotoxins such as aflatoxins.
  • pyrazole compounds of Formula 1 with both a 4-methyl-anilino group as well as a 4-CN-phenyl group have now been discovered to have significantly improved control of certain plant diseases compared to corresponding compounds wherein the aniline ring and the phenyl ring have a hydrogen or halogen (i.e. F, Cl or Br) substituent at the 4- position.
  • compounds of Formula 1 compared to para-halo substituted analogs or analogs with a hydrogen at the para position have been found to provide surprisingly improved antifungal activity against plant fungal diseases, such as Septoria tritici. Because of their extraordinarily desirable biological profile, compounds of Formula 1 are remarkably useful as fungicides alone and in combination with other biologically active compounds or agents.
  • process intermediates useful for preparing compounds of Formula 1, such as compounds of Formulae 17, 20 and 22 are correspondingly particularly useful.
  • Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruits, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing.
  • the compounds can also be applied to seeds to protect the seeds and seedlings developing from the seeds.
  • the compounds can also be applied through irrigation water to treat plants. Control of postharvest pathogens which infect the produce before harvest is typically accomplished by field application of a compound of this invention, and in cases where infection occurs after harvest the compounds can be applied to the harvested crop as dips, sprays, fumigants, treated wraps and box liners. Rates of application for these compounds (i.e.
  • a fungicidally effective amount can be influenced by factors such as the plant diseases to be controlled, the plant species to be protected, ambient moisture and temperature and should be determined under actual use conditions.
  • factors such as the plant diseases to be controlled, the plant species to be protected, ambient moisture and temperature and should be determined under actual use conditions.
  • One skilled in the art can easily determine through simple experimentation the fungicidally effective amount necessary for the desired level of plant disease control.
  • Foliage can normally be protected when treated at a rate of from less than about 1 g/ha to about 5,000 g/ha of active ingredient.
  • Seed and seedlings can normally be protected when seed is treated at a rate of from about 0.1 to about 10 g per kilogram of seed.
  • Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including fungicides, insecticides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection.
  • fungicides insecticides, nematocides, bactericides, acaricides, herbicides, herbicide safeners
  • growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus
  • the present invention also pertains to a composition
  • a composition comprising a compound of Formula 1 (in a fungicidally effective amount) and at least one additional biologically active compound or agent (in a biologically effective amount) and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent.
  • the other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent.
  • one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
  • one aspect of the present invention is a fungicidal composition
  • a fungicidal composition comprising (i.e. a mixture or combination of) a compound of Formula 1, an N-oxide, or a salt thereof (which is identified as component (a)), and at least one other fungicide (which is identified as component (b)).
  • composition which, in addition to the Formula 1 compound of component (a), includes as component (b) at least one fungicidal compound selected from the group consisting of the classes (b1) methyl benzimidazole carbamate (MBC) fungicides; (b2) dicarboximide fungicides; (b3) demethylation inhibitor (DMI) fungicides; (b4) phenylamide fungicides; (b5) amine/morpholine fungicides; (b6) phospholipid biosynthesis inhibitor fungicides; (b7) carboxamide fungicides; (b8) hydroxy(2-amino)pyrimidine fungicides; (b9) anilinopyrimidine fungicides; (b10) N-phenyl carbamate fungicides; (b11) quinone outside inhibitor (QoI) fungicides; (b12) phenylpyrrole fungicides; (b13) quinoline fungicides; (b14) lipid peroxidation inhibitor
  • (b1)“Methyl benzimidazole carbamate (MBC) fungicides” (Fungicide Resistance Action Committee (FRAC) code 1) inhibit mitosis by binding to ⁇ -tubulin during microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure.
  • Methyl benzimidazole carbamate fungicides include benzimidazoles and thiophanates.
  • the benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole.
  • the thiophanates include thiophanate and thiophanate-methyl.
  • b2“Dicarboximide fungicides” (Fungicide Resistance Action Committee (FRAC) code 2) are proposed to inhibit a lipid peroxidation in fungi through interference with NADH cytochrome c reductase.
  • Examples include chlozolinate, iprodione, procymidone and vinclozolin.
  • Demethylation inhibitor (DMI) fungicides (Fungicide Resistance Action Committee (FRAC) code 3) inhibit C14-demethylase, which plays a role in sterol production.
  • Sterols such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi.
  • Demethylation fungicides include piperazines, pyridines, pyrimidines, imidazoles and triazoles.
  • the piperazines include triforine.
  • the pyridines include buthiobate and pyrifenox.
  • the pyrimidines include fenarimol, nuarimol and triarimol.
  • the imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole.
  • the triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, 1-[[
  • the imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole.
  • Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205–258.
  • Phenylamide fungicides include acylalanines, oxazolidinones and butyrolactones.
  • the acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl and metalaxyl- M/mefenoxam.
  • the oxazolidinones include oxadixyl.
  • the butyrolactones include ofurace.
  • Amine/morpholine fungicides include morpholines, piperidines and spiroketal-amines.
  • the morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide.
  • the piperidines include fenpropidin and piperalin.
  • the spiroketal-amines include spiroxamine.
  • Phospholipid biosynthesis inhibitor fungicides include phophorothiolates and dithiolanes.
  • the phosphorothiolates include edifenphos, iprobenfos and pyrazophos.
  • the dithiolanes include isoprothiolane.
  • Carboxamide fungicides include phenyl benzamides, pyridinyl ethyl benzamides, furan carboxamides, oxathiin carboxamides, thiazole carboxamides, pyrazole carboxamides and pyridine carboxamides.
  • the phenyl benzamides include benodanil, flutolanil and mepronil.
  • the pyridinyl ethyl benzamides include fluopyram.
  • the furan carboxamides include fenfuram.
  • the oxathiin carboxamides include carboxin and oxycarboxin.
  • the thiazole carboxamides include thifluzamide.
  • the pyrazole carboxamides include furametpyr, penthiopyrad, bixafen, isopyrazam, benzovindiflupyr, N-[2-(1S,2R)- [1,1'-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, penflufen, (N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbox- amide), N-[2-(2,4-dichlorophenyl)-2-methoxy-1-methylethyl]-3-(difluoromethyl)-1-methyl- 1H-pyrazole-4-carboxamide and N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[[2- (1-methylethyl)phenyl]methyl]-1H-pyrazo
  • b10“N-Phenyl carbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code 10) inhibit mitosis by binding to ⁇ -tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include diethofencarb.
  • Quinone outside inhibitor fungicides include methoxyacrylates, methoxycarbamates, oximinoacetates, oximinoacetamides, oxazolidinediones, dihydrodioxazines, imidazolinones and benzylcarbamates.
  • the methoxyacrylates include azoxystrobin, coumoxystrobin, enestroburin, flufenoxystrobin, picoxystrobin and pyraoxystrobin.
  • the methoxycarbamates include pyraclostrobin, pyrametostrobin and triclopyricarb.
  • the oximinoacetates include kresoxim-methyl and trifloxystrobin.
  • the oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin, ⁇ -[methoxyimino]-N-methyl-2-[[[1-[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyl]benzeneacetamide and 2-[[[3-(2,6-dichlorophenyl)-1-methyl-2-propen-1-ylidene]- amino]oxy]methyl]- ⁇ -(methoxyimino)-N-methylbenzeneacetamide.
  • the oxazolidinediones include famoxadone.
  • the dihydrodioxazines include fluoxastrobin.
  • the imidazolinones include fenamidone.
  • the benzylcarbamates include pyribencarb.
  • Class (11) also includes 2- [(2,5-dimethylphenoxy)methyl]- ⁇ -methoxy-N-benzeneacetamide.
  • Azanaphthalene fungicides include aryloxyquinolines and quinazolinone.
  • the aryloxyquinolines include quinoxyfen and tebufloquin.
  • the quinazolinones include proquinazid.
  • Lipid peroxidation inhibitor fungicides are proposed to inhibit lipid peroxidation which affects membrane synthesis in fungi.
  • Lipid peroxidation fungicides include aromatic carbons and 1,2,4-thiadiazoles.
  • the aromatic carbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos-methyl.
  • the 1,2,4-thiadiazole fungicides include etridiazole.
  • MMI-R Melanin biosynthesis inhibitors-reductase fungicides
  • FRAC Field Action Committee
  • fungicides include isobenzofuranones, pyrroloquinolinones and triazolobenzothiazoles.
  • the isobenzofuranones include fthalide.
  • the pyrroloquinolinones include pyroquilon.
  • the triazolobenzothiazoles include tricyclazole.
  • Melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides include cyclopropanecarboxamides, carboxamides and propionamides.
  • the cyclopropanecarboxamides include carpropamid.
  • the carboxamides include diclocymet.
  • the propionamides include fenoxanil.
  • Squalene-epoxidase inhibitor fungicides include thiocarbamates and allylaminess.
  • the thiocarbamates include pyributicarb.
  • the allylamines include naftifine and terbinafine.
  • Quinone inside inhibitor fungicides include cyanoimidazoles and sulfamoyltriazoles.
  • the cyanoimidazoles include cyazofamid.
  • the sulfamoyltriazoles include amisulbrom.
  • b22 “Benzamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 22) inhibit mitosis by binding to ⁇ -tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include zoxamide.
  • b26 “Glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides” (Fungicide Resistance Action Committee (FRAC) code 26) inhibit trehalase in inositol biosynthesis pathway. Examples include validamycin.
  • This class includes 2,6-dinitroanilines such as fluazinam, pyrimidonehydrazones such as ferimzone and dinitrophenyl crotonates such as dinocap, meptyldinocap and binapacryl.
  • b31 “Carboxylic acid fungicides” (Fungicide Resistance Action Committee (FRAC) code 31) inhibit growth of fungi by affecting deoxyribonucleic acid (DNA) topoisomerase type II (gyrase). Examples include oxolinic acid.
  • Heteroaromatic fungicides include isoxazoles and isothiazolones.
  • the isoxazoles include hymexazole and the isothiazolones include octhilinone.
  • Carboxylic acid amide (CAA) fungicides are proposed to inhibit phospholipid biosynthesis and cell wall deposition. Inhibition of these processes prevents growth and leads to death of the target fungus.
  • Carboxylic acid amide fungicides include cinnamic acid amides, valinamide carbamates, carbamates and mandelic acid amides.
  • the cinnamic acid amides include dimethomorph and flumorph.
  • the valinamide carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, valifenalate and valiphenal.
  • the carbamates include tolprocarb.
  • the mandelic acid amides include mandipropamid, N-[2-[4-[[3-(4- chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(methylsulfonyl)- amino]butanamide and N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]- ethyl]-3-methyl-2-[(ethylsulfonyl)amino]butanamide.
  • b43 “Benzamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 43) inhibit growth of fungi by delocalization of spectrin-like proteins.
  • Examples include acylpicolide fungicides such as fluopicolide.
  • Host plant defense induction fungicides include benzothiadiazoles, benzisothiazoles and thiadiazolecarboxamides.
  • the benzothiadiazoles include acibenzolar-S-methyl.
  • the benzisothiazoles include probenazole.
  • the thiadiazolecarboxamides include tiadinil and isotianil.
  • (b45)“Multi-site contact fungicides” inhibit fungal growth through multiple sites of action and have contact/preventive activity.
  • This class of fungicides includes: (b45.1) “copper fungicides” (Fungicide Resistance Action Committee (FRAC) code M1)”, (b45.2) “sulfur fungicides” (Fungicide Resistance Action Committee (FRAC) code M2), (b45.3) “dithiocarbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code M3), (b45.4)“phthalimide fungicides” (Fungicide Resistance Action Committee (FRAC) code M4), (b45.5)“chloronitrile fungicides” (Fungicide Resistance Action Committee (FRAC) code M5), (b45.6)“sulfamide fungicides” (Fungicide Resistance Action Committee (FRAC) code M6), (b45.7)“guanidine fungicides” (Fungicide Resistance Action Committee (FRAC) code M7), (b
  • Copper fungicides are inorganic compounds containing copper, typically in the copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate).
  • Sulfur fungicides are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur.
  • “Dithiocarbamate fungicides” contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, maneb, thiram, zineb and ziram.“Phthalimide fungicides” contain a phthalimide molecular moiety; examples include folpet, captan and captafol.“Chloronitrile fungicides” contain an aromatic ring substituted with chloro and cyano; examples include chlorothalonil. “Sulfamide fungicides” include dichlofluanid and tolyfluanid.
  • “Guanidine fungicides” include dodine, guazatine, iminoctadine albesilate and iminoctadine triacetate. “Triazine fungicides” include anilazine.“Quinone fungicides” include dithianon.
  • (b46)“Fungicides other than fungicides of classes (b1) through (b45)” include certain fungicides whose mode of action may be unknown. These include: (b46.1)“thiazole carboxamide fungicides” (Fungicide Resistance Action Committee (FRAC) code U5), (b46.2)“phenylacetamide fungicides” (Fungicide Resistance Action Committee (FRAC) code U6), (b46.3)“arylphenylketone fungicides” (Fungicide Resistance Action Committee (FRAC) code U8) and (b46.4)“triazolopyrimidine fungicides”.
  • the thiazole carboxamides include ethaboxam.
  • the phenylacetamides include cyflufenamid and N- [[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]- benzeneacetamide.
  • the arylphenylketones include benzophenones such as metrafenone and benzoylpyridines such as pyriofenone.
  • the triazolopyrimidines include ametoctradin.
  • Class (b46) (i.e.“Fungicides other than classes (b1) through (b45)”) also includes bethoxazin, fluxapyroxad, neo-asozin (ferric methanearsonate), pyrrolnitrin, quinomethionate, tebufloquin, isofetamid, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxy- phenyl]ethyl]-3-methyl-2-[(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chloro- phenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(ethylsulfonyl)amino]- butanamide, 2-[[2-fluoro-5-(trifluoro
  • a mixture i.e. composition
  • component (a) a compound of Formula 1 (or an N-oxide or salt thereof) and as component (b) at least one fungicidal compound selected from the group consisting of the aforedescribed classes (b1) through (b46).
  • component (b) comprises at least one fungicide from each of two different groups selected from (b1) through (b46).
  • a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • a mixture i.e.
  • composition comprising a compound of Formula 1 and at least one fungicidal compound selected from the group of specific compounds listed above in connection with classes (b1) through (b46). Also of particular note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional surfactant selected from the group consisting of surfactants, solid diluents and liquid diluents.
  • insecticides such as abamectin, acephate, acetamiprid, acrinathrin, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, carbofuran, cartap, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyantraniliprole (3-bromo- 1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H- pyrazole-5-carboxamide), cyflumetofen, cyfluthrin, beta-c
  • Bacillus thuringiensis subsp. kurstaki, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi, such as green muscardine fungus; and entomopathogenic virus including baculovirus, nucleopolyhedro virus (NPV) such as HzNPV, AfNPV; and granulosis virus (GV) such as CpGV.
  • NPV nucleopolyhedro virus
  • GV granulosis virus
  • insecticides include The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2003 and The BioPesticide Manual, 2nd Edition, L. G. Copping, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2001.
  • the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1:3000 and about 3000:1. Of note are weight ratios between about 1:300 and about 300:1 (for example ratios between about 1:30 and about 30:1).
  • weight ratios between about 1:300 and about 300:1 for example ratios between about 1:30 and about 30:1.
  • One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of diseases controlled beyond the spectrum controlled by the compound of Formula 1 alone.
  • combinations of a compound of this invention with other biologically active (particularly fungicidal) compounds or agents can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable.
  • synergism of fungicidal active ingredients occurs at application rates giving agronomically satisfactory levels of fungal control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
  • Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis delta-endotoxins).
  • proteins toxic to invertebrate pests such as Bacillus thuringiensis delta-endotoxins.
  • the effect of the exogenously applied fungicidal compounds of this invention may be synergistic with the expressed toxin proteins.
  • a combination of a compound of Formula 1 with at least one other fungicidal active ingredient is such a combination where the other fungicidal active ingredient has different site of action from the compound of Formula 1.
  • a combination with at least one other fungicidal active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management.
  • a composition of the present invention can further comprise a biologically effective amount of at least one additional fungicidal active ingredient having a similar spectrum of control but a different site of action.
  • compositions which in addition to a compound of Formula 1 include at least one compound selected from the group consisting of (1) alkylenebis(dithiocarbamate) fungicides; (2) cymoxanil; (3) phenylamide fungicides; (4) proquinazid (6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone); (5) chlorothalonil; (6) carboxamides acting at complex II of the fungal mitochondrial respiratory electron transfer site; (7) quinoxyfen; (8) metrafenone; (9) cyflufenamid; (10) cyprodinil; (11) copper compounds; (12) phthalimide fungicides; (13) fosetyl-aluminum; (14) benzimidazole fungicides; (15) cyazofamid; (16) fluazinam; (17) iprovalicarb; (18) propamocarb; (19) validomycin; (20) dich
  • Alkylenebis(dithiocarbamate)s include compounds such as mancozeb, maneb, propineb and zineb.
  • Phenylamides include compounds such as metalaxyl, benalaxyl, furalaxyl and oxadixyl.
  • Carboxamides include compounds such as boscalid, carboxin, fenfuram, flutolanil, furametpyr, mepronil, oxycarboxin, thifluzamide, penthiopyrad and N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H- pyrazole-4-carboxamide (PCT Patent Publication WO 2003/010149), and are known to inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain.
  • complex II succinate dehydrogenase
  • Copper compounds include compounds such as copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate).
  • Phthalimides include compounds such as folpet and captan.
  • Benzimidazole fungicides include benomyl and carbendazim.
  • Dichlorophenyl dicarboximide fungicides include chlozolinate, dichlozoline, iprodione, isovaledione, myclozolin, procymidone and vinclozolin.
  • Sterol biosynthesis inhibitors control fungi by inhibiting enzymes in the sterol biosynthesis pathway.
  • Demethylase-inhibiting fungicides have a common site of action within the fungal sterol biosynthesis pathway, involving inhibition of demethylation at position 14 of lanosterol or 24-methylene dihydrolanosterol, which are precursors to sterols in fungi. Compounds acting at this site are often referred to as demethylase inhibitors, DMI fungicides, or DMIs.
  • the demethylase enzyme is sometimes referred to by other names in the biochemical literature, including cytochrome P-450 (14DM). The demethylase enzyme is described in, for example, J. Biol. Chem.
  • DMI fungicides are divided between several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines.
  • the triazoles include azaconazole, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and unicon
  • the imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole, oxpoconazole, prochloraz and triflumizole.
  • the pyrimidines include fenarimol, nuarimol and triarimol.
  • the piperazines include triforine.
  • the pyridines include buthiobate and pyrifenox. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
  • Non-DMI sterol biosynthesis inhibitors include morpholine and piperidine fungicides.
  • the morpholines and piperidines are sterol biosynthesis inhibitors that have been shown to inhibit steps in the sterol biosynthesis pathway at a point later than the inhibitions achieved by the DMI sterol biosynthesis (group (27)).
  • the morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide.
  • the piperidines include fenpropidin.
  • b c 1 Complex Fungicides (group 28) have a fungicidal mode of action which inhibits the bc 1 complex in the mitochondrial respiration chain.
  • the bc 1 complex is sometimes referred to by other names in the biochemical literature, including complex III of the electron transfer chain, and ubihydroquinone:cytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number EC1.10.2.2.
  • the bc 1 complex is described in, for example, J. Biol. Chem. 1989, 264, 14543-48; Methods Enzymol. 1986, 126, 253–71; and references cited therein.
  • Strobilurin fungicides such as azoxystrobin, dimoxystrobin, enestroburin (SYP-Z071), fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin and trifloxystrobin are known to have this mode of action (H. Sauter et al., Angew. Chem. Int. Ed. 1999, 38, 1328-1349).
  • Other fungicidal compounds that inhibit the bc 1 complex in the mitochondrial respiration chain include famoxadone and fenamidone.
  • component (b) fungicides include acibenzolar-S-methyl, aldimorph, ametoctradin, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl, benalaxyl-M, benodanil, benomyl, benthiavalicarb, benthiavalicarb-isopropyl, bethoxazin, binapacryl, biphenyl, bitertanol, bixafen, blasticidin-S, boscalid, bromuconazole, bupirimate, carboxin, carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil, chlozolinate, clotrimazole, copper salts such as Bordeaux mixture (tribasic copper sulfate), copper hydroxide and copper oxychloride, cyazofamid, cyfluf
  • Preferred for better control of plant diseases caused by fungal plant pathogens are mixtures of a compound of this invention with a fungicide selected from the group: azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, pyrametostrobin, pyraoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, cyproconazole, epoxiconazole, flusilazole, metconazole, propiconazole, proquinazid, prothioconazole, pyriofenone, tebuconazole, triticonazole, famoxadone and penthiopyrad.
  • azoxystrobin kresoxim-methyl
  • trifloxystrobin e.g.,
  • Table A1 lists specific combinations of a component (b) compound with Compound 1 (Index Table A) as component (a) illustrative of the mixtures, compositions and methods of the present invention.
  • Compound numbers refer to compounds in Index Table A.
  • the second column of Table A1 lists ranges of Typical Weight Ratios the component (b) compound (e.g., acibenzolar-S-methyl in the first line) is applied with Compound 1 as component (a).
  • the third and fourth columns of Table A1 list ranges of weight ratios for rates at which the component (a) compound is More Typically and Most Typically applied to a field-grown crop relative to component (b).
  • the fifth column of Table A1 lists an Illustrative Weight Ratio for rates at which the component (a) compound is typically applied to a field-grown crop relative to component (b).
  • the first line of Table A1 specifically discloses the combination of acibenzolar-S-methyl with Compound 1 is typically applied in a weight ratio of acibenzolar-S-methyl to Compound 1 of between 2:1 and 1:180 (i.e.
  • Table A1 The remaining lines of Table A1 are to be construed similarly.
  • Tables A2 through A12 are each constructed the same as Table A1 above except that the entry under the row heading“Component (a)” in Table A1” is replaced with the res ective entries under the row headin “Com onent a” shown below.
  • M the n umerical value reported in the column “AP - (M-1)”, is the molecular weight of the observed molecular ion formed by loss of H + (molecular weight of 1) from the molecule having the greatest isotopic abundance (i.e. M).
  • the reported M+1 and M-1 peaks were observed by mass spectrometry using atmospheric pressure chemical ionization (AP+).
  • test suspensions for Tests A-E were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mix by volume) containing 250 ppm of the surfactant Trem ® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-E.
  • test suspension was sprayed to the point of run-off on wheat seedlings.
  • seedlings were inoculated with a spore suspension of Puccinia recondita f. sp. tritici (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20 °C for 24 h, and then moved to a growth chamber at 20 °C for 7 days, after which time visual disease ratings were made.
  • test suspension was sprayed to the point of run-off on wheat seedlings.
  • seedlings were inoculated with a spore suspension of Septoria tritici (the causal agent of wheat leaf blotch) and incubated in a saturated atmosphere at 24 °C for 48 h, and then moved to a growth chamber at 20 °C for 19 days, after which time visual disease ratings were made.
  • test suspension was sprayed to the point of run-off on tomato seedlings.
  • seedlings were inoculated with a spore suspension of Botrytis cinerea (the causal agent of tomato Botrytis) and incubated in a saturated atmosphere at 20 °C for 48 h, and then moved to a growth chamber at 24 °C for 3 days, after which time visual disease ratings were made.
  • Botrytis cinerea the causal agent of tomato Botrytis
  • test suspension was sprayed to the point of run-off on wheat seedlings.
  • seedlings were inoculated with a spore dust of Blumeria graminis f. sp. tritici, (also known as Erysiphe graminis f. sp. tritici, the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20 °C for 8 days, after which time visual disease ratings were made.
  • Blumeria graminis f. sp. tritici also known as Erysiphe graminis f. sp. tritici, the causal agent of wheat powdery mildew
  • test solution was sprayed to the point of run-off on soybean seedlings.
  • seedlings were inoculated with a spore suspension of Phakopsora pachyrhizi (the causal agent of Asian soybean rust) and incubated in a saturated atmosphere at 22 °C for 24 h and then moved to a growth chamber at 22 °C for 8 days, after which time visual disease ratings were made.
  • Phakopsora pachyrhizi the causal agent of Asian soybean rust
  • Results for Tests A-E are given in Table A below.
  • a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls).
  • a dash (–) indicates no test results.

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Abstract

Disclosed are compounds of Formula (1), including all geometric and stereoisomers, N oxides, and salts thereof, wherein R1, R2, R3, R4 and X are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling plant disease caused by a fungal pathogen comprising applying an effective amount of a compound or a composition of the invention.

Description

TITLE
FUNGICIDAL PYRAZOLES FIELD OF THE INVENTION
This invention relates to certain pyrazoles, their N-oxides, salts and compositions, and methods of their use as fungicides.
BACKGROUND OF THE INVENTION
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different sites of action.
PCT Patent Publications WO 2009/137538, WO 2009/137651, WO 2010/101973, WO 2012/023143, WO 2012/031061, WO 2013/116251, WO 2013/126283, WO 2013/192126 and WO 2014/130241 disclose pyrazole derivatives and their use as fungicides.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula 1 (including all stereoisomers), N-oxides, and salts thereof, agricultural compositions containing them and their use as fungicides:
Figure imgf000002_0001
wherein
R1 is halogen;
R2 is H or halogen;
R3 is halogen;
R4 is H or halogen;
X is NR 5 or CR 6 OR 7 ;
R5 is H, amino, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -CH(=O), -SO - 3 M+, -S(=O)mR8, -C(=W)R9 or OR10; or C1-C6 alkyl or C1-C6 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R11 ;
R6 is H or C 1 -C 6 alkyl;
R7 is H, amino, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -CH(=O),
-SO - 3 M+, -S(=O) m R8 or -C(=W)R9; or C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 ; R8 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
R9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 3 -C 6
dialkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy C 2 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl; R10 is H, -CH(=O), C3-C6 cycloalkyl, -SO –
3 M + or -C(=W)R 12 ; or C1-C6 alkyl or C1 -C 6 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 13 ;
each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl;
R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 3 -C 6
dialkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl; each R13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl;
W is O or S;
M+ is K, Na or Li; and
m is 0, 1 or 2.
More particularly, this invention pertains to a compound selected from compounds of Formula 1 (including all stereoisomers) and N-oxides and salts thereof.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention (i.e. in a fungicidally effective amount); and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
This invention also relates to a fungicidal composition comprising (a) a compound of the invention; and (b) at least one other fungicide (e.g., at least one other fungicide having a different site of action).
This invention further relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of the invention (e.g., as a composition described herein). This invention also relates to a composition comprising a compound of Formula 1, an N-oxide, or a salt thereof, and at least one invertebrate pest control compound or agent.
DETAILS OF THE INVENTION
As used herein, the terms“comprises,”“comprising,”“includes,”“including,”“has,” “having,”“contains,”“containing,”“characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
The transitional phrase“consisting of” excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of” appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.
The transitional phrase“consisting essentially of” is used to define a composition, method or apparatus that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term“consisting essentially of” occupies a middle ground between “comprising” and“consisting of”.
Where applicants have defined an invention or a portion thereof with an open-ended term such as“comprising,” it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms “consisting essentially of” or“consisting of.”
Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles“a” and“an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore“a” or“an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
As referred to in the present disclosure and claims,“plant” includes members of Kingdom Plantae, particularly seed plants (Spermatopsida), at all life stages, including young plants (e.g., germinating seeds developing into seedlings) and mature, reproductive stages (e.g., plants producing flowers and seeds). Portions of plants include geotropic members typically growing beneath the surface of the growing medium (e.g., soil), such as roots, tubers, bulbs and corms, and also members growing above the growing medium, such as foliage (including stems and leaves), flowers, fruits and seeds.
As referred to herein, the term“seedling”, used either alone or in a combination of words means a young plant developing from the embryo of a seed.
As referred to herein, the term“broadleaf” used either alone or in words such as “broadleaf crop” means dicot or dicotyledon, a term used to describe a group of angiosperms characterized by embryos having two cotyledons.
As used herein, the term“alkylating agent” refers to a chemical compound in which a carbon-containing radical is bound through a carbon atom to a leaving group such as halide or sulfonate, which is displaceable by bonding of a nucleophile to said carbon atom. Unless otherwise indicated, the term“alkylating agent” or“alkylating reagent” does not limit the carbon-containing radical to alkyl; the carbon-containing radicals in alkylating agents include the variety of carbon-bound substituent radicals specified, for example, for R 5 .
Generally when a molecular fragment (i.e. radical) is denoted by a series of atom symbols (e.g., C, H, N, O, S) the implicit point or points of attachment will be easily recognized by those skilled in the art. In some instances herein, particularly when alternative points of attachment are possible, the point or points of attachment may be explicitly indicated by a hyphen (“-”).
In the above recitations, the term“alkyl”, used either alone or in compound words such as“alkylthio” or“haloalkyl” includes straight-chain or branched alkyl such as methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. “Alkenyl” includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.“Alkynyl” includes straight-chain or branched alkynes such as 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. “Alkynyl” can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
“Alkylamino” includes an NH radical substituted with straight-chain or branched alkyl. Examples of “alkylamino” include CH 3 CH 2 NH, CH 3 CH 2 CH 2 NH and (CH 3 ) 2 CHNH. Examples of “dialkylamino” include (CH 3 ) 2 N, (CH 3 CH 2 ) 2 N and CH 3 CH 2 (CH 3 )N. “Alkylaminoalkyl” denotes alkylamino substitution on alkyl. Examples of “alkylaminoalkyl” include CH 3 NHCH 2 , CH 3 NHCH 2 CH 2 and CH 3 CH 2 NHCH 2 . Examples of“dialkylaminoalkyl” include (CH 3 ) 2 NCH 2 , CH 3 CH 2 (CH 3 )NCH 2 and (CH 3 ) 2 NCH 2 CH 2 . “Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy, i-propyloxy and the different butoxy, pentoxy and hexyloxy isomers.“Alkoxyalkyl” denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 . “Alkenyloxy” includes straight-chain or branched alkenyl attached to and linked through an oxygen atom. Examples of“alkenyloxy” include H 2 C=CHCH 2 O, (CH 3 ) 2 C=CHCH 2 O, CH 3 CH=CHCH 2 O, CH 3 CH=C(CH 3 )CH 2 O and CH 2 =CHCH 2 CH 2 O. “Alkynyloxy” includes straight-chain or branched alkynyl attached to and linked through an oxygen atom. Examples of “alkynyloxy” include HC ^CCH 2 O, CH 3 C ^CCH 2 O and CH 3 C ^CCH 2 CH 2 O.
“Alkylthio” includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio isomers. “Alkylthioalkyl” denotes alkylthio substitution on alkyl. Examples of “alkylthioalkyl” include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 . “Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group. Examples of“alkylsulfinyl” include CH 3 S(=O), CH 3 CH 2 S(=O), CH 3 CH 2 CH 2 S(=O) and (CH 3 ) 2 CHS(=O). Examples of “alkylsulfonyl” include CH 3 S(=O) 2 , CH 3 CH 2 S(=O) 2 , CH 3 CH 2 CH 2 S(=O) 2 and (CH 3 ) 2 CHS(=O) 2 .
The term“cycloalkyl” denotes a saturated carbocyclic ring consisting of between 3 to 7 carbon atoms linked to one another by single bonds. Examples of“cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term“cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl group. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
“Alkylcarbonyl” denotes a straight-chain or branched alkyl group bonded to a C(=O) moiety. Examples of “alkylcarbonyl” include CH 3 C(=O), CH 3 CH 2 CH 2 C(=O) and (CH 3 ) 2 CHC(=O). Examples of “alkoxycarbonyl” include CH 3 OC(=O), CH 3 CH 2 OC(=O), CH 3 CH 2 CH 2 OC(=O), (CH 3 ) 2 CHOC(=O) and the different pentoxy- or hexoxycarbonyl isomers. The term“alkylcarbonyloxy” denotes straight-chain or branched alkyl bonded to a C(=O)O moiety. Examples of “alkylcarbonyloxy” include CH 3 CH 2 C(=O)O and (CH 3 ) 2 CHC(=O)O. “(Alkylthio)carbonyl” denotes a straight-chain or branched alkylthio group bonded to a C(=O) moiety. Examples of “(alkylthio)carbonyl” include CH 3 SC(=O), CH 3 CH 2 CH 2 SC(=O) and (CH 3 ) 2 CHSC(=O). “Alkoxy(thiocarbonyl)” denotes a straight-chain or branched alkoxy group bonded to a C(=S) moiety.
The term“halogen”, either alone or in compound words such as“halomethyl”, “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as“haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, ClCH 2 , CF 3 CH 2 and CF 3 CCl 2 . The term “haloalkoxy” is defined analogously to the term “haloalkyl”. Examples of “haloalkoxy” include CF 3 O, CCl 3 CH 2 O, F 2 CHCH 2 CH 2 O and CF 3 CH 2 O.
The total number of carbon atoms in a substituent group is indicated by the“C i -C j ” prefix where i and j are numbers from 1 to 8. For example, C 1 -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C 2 alkoxyalkyl designates CH 3 OCH 2 ; C 3 alkoxyalkyl designates, for example, CH 3 OCH 2 CH 2 or CH 3 CH 2 OCH 2 ; and C 4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
The term“unsubstituted” in connection with a group such as a ring means the group does not have any substituents other than its one or more attachments to the remainder of Formula 1. The term“optionally substituted” means that the number of substituents can be zero. Unless otherwise indicated, optionally substituted groups may be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, the number of optional substituents (when present) range from 1 to 3. As used herein, the term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” or with the term“(un)substituted.”
The number of optional substituents may be restricted by an expressed limitation. For example, the phrase“optionally substituted with up to 2 substituents independently selected from R 11 ” means that 0, 1 or 2 substituents can be present (if the number of potential connection points allows).
The terms“carbocyclic ring” or“carbocycle” denote a ring wherein the atoms forming the ring backbone are selected only from carbon. When a fully unsaturated carbocyclic ring satisfies Hückel’s rule, then said ring is also called an“aromatic carbocyclic ring”. The term “saturated carbocyclic ring” refers to a ring having a backbone consisting of carbon atoms linked to one another by single bonds; unless otherwise specified, the remaining carbon valences are occupied by hydrogen atoms.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form.
One skilled in the art recognizes that because in the environment and under physiological conditions salts of chemical compounds are in equilibrium with their corresponding nonsalt forms, salts share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of Formula 1 are useful for control of plant diseases caused by fungal plant pathogens (i.e. are agriculturally suitable). The salts of the compounds of Formula 1 include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
Compounds selected from Formula 1, stereoisomers, N-oxides, and salts thereof, typically exist in more than one form, therefore Formula 1 includes all crystalline and non- crystalline forms of the compounds that Formula 1 represents. Non-crystalline forms include embodiments which are solids such as waxes and gums as well as embodiments which are liquids such as solutions and melts. Crystalline forms include embodiments which represent essentially a single crystal type and embodiments which represent a mixture of polymorphs (i.e. different crystalline types). The term“polymorph” refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules, which can be weakly or strongly bound in the lattice. Polymorphs can differ in such chemical, physical and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph of a compound represented by Formula 1 can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved biological performance) relative to another polymorph or a mixture of polymorphs of the same compound represented by Formula 1. Preparation and isolation of a particular polymorph of a compound represented by Formula 1 can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures.
Embodiments of the present invention as described in the Summary of the Invention include those described below. In the following Embodiments, Formula 1 includes stereoisomers, N-oxides and salts thereof, and reference to“a compound of Formula 1” includes the definitions of substituents specified in the Summary of the Invention unless further defined in the Embodiments.
Embodiment 1. A compound of Formula 1 wherein X is NR 5 .
Embodiment 2. A compound of Embodiment 1 wherein X is NH.
Embodiment 3. A compound of Formula 1 wherein X is CR 6 OR 7 .
Embodiment 4. A compound of Embodiment 3 wherein X is CHOH.
Embodiment 5. A compound of Formula 1 wherein X is NH or CHOH.
Embodiment 6. A compound of Formula 1 or any one of Embodiments 1 through 5 wherein R 1 is Br, Cl or F.
Embodiment 7. A compound of Embodiment 6 wherein R 1 is Br or Cl.
Embodiment 8. A compound of Formula 1 or any one of Embodiments 1 through 7 wherein R 2 is halogen. Embodiment 9. A compound of Embodiment 8 wherein R 2 is Br, Cl or F.
Embodiment 10. A compound of Embodiment 9 wherein R 2 is Cl or F.
Embodiment 11. A compound of Formula 1 or any one of Embodiments 1 through 7 wherein R 2 is H, Br, Cl or F.
Embodiment 12. A compound of Embodiment 11 wherein R 2 is H, Cl or F.
Embodiment 13. A compound of Embodiment 12 wherein R 2 is H.
Embodiment 14. A compound of Formula 1 or any one of Embodiments 1 through 13 wherein R 3 is Br, Cl or F.
Embodiment 15. A compound of Formula 1 or any one of Embodiments 1 through 14 wherein R 4 is H.
Embodiment 16. A compound of Formula 1 or any one of Embodiments 1 through 14 wherein R 4 is halogen.
Embodiment 17. A compound of Embodiment 16 wherein R 4 is Br, Cl or F.
Embodiment 18. A compound of Embodiment 17 wherein R 4 is Cl or F.
Embodiment 19. A compound of Embodiment 18 wherein R 4 is F.
Embodiment 20. A compound of Formula 1 or any one of Embodiments 1 through 14 wherein R 4 is H, Br, Cl or F.
Embodiment 21. A compound of Embodiment 20 wherein R 4 is H, Cl or F.
Embodiment 22. A compound of Embodiment 21 wherein R 4 is H or F.
Embodiment 23. A compound of Formula 1 or any one of Embodiments 1 through 22 wherein R5 is H, C 2 -C 3 alkenyl, C 3 -C 4 alkynyl, cyclopropyl, -CH(=O),
-S(=O) m R8, -C(=W)R9 or OR10; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 . Embodiment 24. A compound of Embodiment 23 wherein R 5 is H,
cyclopropyl, -CH(=O), -C(=W)R9 or OR10; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 11 .
Embodiment 25. A compound of Embodiment 24 wherein R 5 is
H, -CH(=O), -C(=W)R9, OR10, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
Embodiment 26. A compound of Embodiment 25 wherein R 5 is H, -CH(=O), OR 10 , C1 -C 3 alkyl or C 1 -C 3 haloalkyl.
Embodiment 27. A compound of Embodiment 26 wherein R 5 is H, -CH(=O), methyl or methoxy.
Embodiment 28. A compound of Embodiment 27 wherein R 5 is H.
Embodiment 29. A compound of Formula 1 or any one of Embodiments 1 through 28 wherein R 6 is H or methyl.
Embodiment 30. A compound of Embodiment 29 wherein R 6 is H.
Embodiment 31. A compound of Formula 1 or any one of Embodiments 1 through 30 wherein R7 is H, -CH(=O) or -C(=W)R9; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R11 .
Embodiment 32. A compound of Embodiment 31 wherein R 7 is H, -CH(=O)
or -C(=W)R9; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 11 .
Embodiment 33. A compound of Embodiment 32 wherein R 7 is H, -CH(=O),
-C(=W)R9, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
Embodiment 34. A compound of Embodiment 33 wherein R 7 is H, -CH(=O),
-C(=W)R 9 , methyl or halomethyl.
Embodiment 35. A compound of Embodiment 34 wherein R 7 is H.
Embodiment 36. A compound of Formula 1 or any one of Embodiments 1 through 35 wherein R 8 is methyl or halomethyl.
Embodiment 37. A compound of Formula 1 or any one of Embodiments 1 through 36 wherein R9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
Embodiment 38. A compound of Embodiment 37 wherein R9 is C 1 -C 3 alkyl, C 2 -C 4 alkoxyalkyl, C 4 -C 6 cycloalkylalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyloxy C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl.
Embodiment 39. A compound of Embodiment 38 wherein R9 is C 1 -C 3 alkyl, C 2 -C 3 alkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyloxy or C 1 -C 3 alkylthio.
Embodiment 40. A compound of Embodiment 39 wherein R 9 is methyl, ethyl,
methoxy, ethoxy, methylthio or ethylthio.
Embodiment 41. A compound of Embodiment 40 wherein R9 is methyl, methoxy or methylthio.
Embodiment 42. A compound of Formula 1 or any one of Embodiments 1 through 41 wherein R10 is H, -CH(=O), C3-C6 cycloalkyl or -C(=W)R12; or C1-C3 alkyl or C1 -C 3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 13 .
Embodiment 43. A compound of Embodiment 42 wherein R 10 is H, -CH(=O),
cyclopropyl, -C(=W)R12, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
Embodiment 44. A compound of Embodiment 43 wherein R 10 is cyclopropyl, methyl or ethyl.
Embodiment 45. A compound of Formula 1 or any one of Embodiments 1 through 44 wherein each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio. Embodiment 46. A compound of Embodiment 45 wherein each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio. Embodiment 47. A compound of Embodiment 46 wherein each R 11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
Embodiment 48. A compound of Embodiment 47 wherein each R 11 is independently cyano, cyclopropyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
Embodiment 49. A compound of Embodiment 48 wherein each R 11 is independently cyano, cyclopropyl, methoxy or methylthio.
Embodiment 50. A compound of Formula 1 or any one of Embodiments 1 through 49 wherein R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
Embodiment 51. A compound of Embodiment 50 wherein R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
Embodiment 52. A compound of Embodiment 51 wherein R12 is C 1 -C 3 alkyl, C 2 -C 4 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 3 alkoxy, C 2 -C 4 alkenyloxy, C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl.
Embodiment 53. A compound of Embodiment 52 wherein R12 is C 1 -C 3 alkyl, C 2 -C 4 alkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl.
Embodiment 54. A compound of Embodiment 53 wherein R 12 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
Embodiment 55. A compound of Embodiment 54 wherein R 12 is methyl, methoxy or methylthio.
Embodiment 56. A compound of Formula 1 or any one of Embodiments 1 through 55 wherein each R13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio.
Embodiment 57. A compound of Embodiment 56 wherein each R 13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio. Embodiment 58. A compound of Embodiment 57 wherein each R 13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
Embodiment 59. A compound of Embodiment 58 wherein each R 13 is independently cyano, cyclopropyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio.
Embodiment 60. A compound of Embodiment 59 wherein each R 13 is independently cyano, cyclopropyl, methoxy or methylthio.
Embodiment 61. A compound of Formula 1 or any one of Embodiments 1 through 60 wherein W is O. Embodiment 62. A compound of Formula 1 or any one of Embodiments 1 through 61 wherein M + is K or Na.
Embodiment 63. A compound of Formula 1 or any one of Embodiments 1 through 62 wherein m is 0.
Embodiment 64. A compound of Formula 1 or any one of Embodiments 1 through 63 wherein R 1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is H; or
R1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is F; or
R1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is H; or
R1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is F.
Embodiments of this invention, including Embodiments 1-64 above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1. In addition, embodiments of this invention, including Embodiments 1-64 above as well as any other embodiments described herein, and any combination thereof, pertain to the compositions and methods of the present invention.
Combinations of Embodiments 1-64 are illustrated by:
Embodiment A. A compound of Formula 1 wherein
R1 is Br, Cl or F;
R2 is halogen;
R3 is Br, Cl or F;
R4 is H, Br, Cl or F;
R5 is H, C 2 -C 3 alkenyl, C 3 -C 4 alkynyl, cyclopropyl, -CH(=O),
-S(=O) m R8, -C(=W)R9 or OR10; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 ;
R6 is H or methyl;
R7 is H, -CH(=O) or -C(=W)R9; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 ;
R8 is methyl or halomethyl;
R9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl;
R10 is H, -CH(=O), C 3 -C 6 cycloalkyl or -C(=W)R12; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 13 ; each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio;
R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl;
R13 is cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio; and
W is O.
Embodiment B. A compound of Embodiment A wherein
R2 is Br, Cl or F;
R5 is H, cyclopropyl, -CH(=O), -C(=W)R9 or OR10; or C1-C3 alkyl or C1-C3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 11 ;
R7 is H, -CH(=O) or -C(=W)R9; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 11 ;
R9 is C 1 -C 3 alkyl, C 2 -C 4 alkoxyalkyl, C 4 -C 6 cycloalkylalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyloxy C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl;
R10 is H, -CH(=O), cyclopropyl, -C(=W)R12, C1-C3 alkyl or C1-C3 haloalkyl; R11 is cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio; and
R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
Embodiment C. A compound of Embodiment B wherein
R5 is H, -CH(=O), -C(=W)R9, OR10, C1-C3 alkyl or C1-C3 haloalkyl; R6 is H;
R7 is H, -CH(=O), -C(=W)R9, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
R9 is C 1 -C 3 alkyl, C 2 -C 3 alkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy,
C2 -C 4 alkenyloxy or C 1 -C 3 alkylthio; and
R10 is cyclopropyl, methyl or ethyl.
Embodiment D. A compound of Embodiment C wherein
R1 is Br or Cl;
R2 is Cl or F;
R4 is H or F;
R5 is H, -CH(=O), methyl or methoxy;
R7 is H, -CH(=O), -C(=W)R 9 , methyl or halomethyl; and
R9 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
Embodiment E. A compound of Embodiment C or Formula 1 wherein X is NH;
R1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is H; or
R1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is F; or
R1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is H; or
R1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is F.
Specific embodiments include compounds of Formula 1 selected from the group consisting of:
4-[5-[(2,6-dichloro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3,5- difluorobenzonitrile (Compound 1);
4-[5-[(2,6-dichloro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3- fluorobenzonitrile (Compound 5);
4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3,5- difluorobenzonitrile (Compound 8);
4-[5-[(2-chloro-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3,5- difluorobenzonitrile (Compound 9); and
4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3- chlorobenzonitrile (Compound 11).
One or more of the following methods and variations as described in Schemes 1-21 can be used to prepare the compounds of Formula 1. The definitions of X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 in the compounds of Formulae 1-31 below are as defined above in the Summary of the Invention unless otherwise noted. Formulae 1a and 1b are various subsets of Formula 1. Substituents for each subset formula are as defined for its parent formula unless otherwise noted.
As shown in Scheme 1, compounds of Formula 1 can be prepared by reaction of 1H-pyrazole compounds of Formula 2 with methylating agents of formula CH3-L1 wherein L 1 is a leaving group such as halogen (e.g., Cl, Br, I), sulfonate (e.g., mesylate (OS(O) 2 CH 3 ), triflate (OS(O) 2 CF 3 ), or p-toluenesulfonate) or phosphate (e.g., dimethyl phosphate), preferably in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate or potassium hydroxide, and in a solvent such as N,N- dimethylformamide, tetrahydrofuran, toluene or water. General procedures for methylations of this type are well-known in the art and can be readily adapted to prepare compounds of the present invention. Particularly useful methylating agents include diazomethane and iodomethane using general procedures known in the art, such as those described in Canada Journal of Chemistry 1986, 64, 2211-2219 and Heterocycles 2000, 53(12), 2775-2780.
Figure imgf000015_0001
As shown in Scheme 2, compounds of Formula 1a (i.e. Formula 1 wherein X is NR 5 ) can be prepared by reaction of compounds of Formula 3 with compounds of Formula 4 wherein L 2 is a leaving group such as halogen (e.g., Cl, Br, I) or sulfonate (e.g., mesylate (OS(O) 2 CH 3 ), triflate (OS(O) 2 CF 3 ) or p-toluenesulfonate), optionally in the presence of a metal catalyst, and generally in the presence of a base and a polar aprotic solvent such as N,N-dimethylformamide or dimethyl sulfoxide. In certain instances, the use of a metal catalyst in amounts ranging from catalytic up to superstoichiometric can facilitate the desired reaction. For example, the reaction can be run in the presence of a metal catalyst such as copper salt complexes (e.g., CuI with N,N'-dimethylethylenediamine, proline or bipyridyl), palladium complexes (e.g., tris(dibenzylideneacetone)dipalladium(0)) or palladium salts (e.g., palladium acetate) with ligands such as 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl or 2,2'-bis- (diphenylphosphino)1,1'-binaphthalene, with a base such as potassium carbonate, cesium carbonate, potassium phosphate, sodium phenoxide or sodium tert-butoxide and a solvent such as N,N-dimethylformamide, 1,2-dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane or toluene, optionally containing an alcohol such as ethanol. For relevant references, see PCT Patent Publications WO 2013/126283, Synthesis Example 1, Step C; and WO 2010/020363, Example 2A.
Figure imgf000016_0001
Alternatively, as illustrated in Scheme 3, compounds of Formula 1a can be prepared by reaction of compounds of Formula 5 with compounds of Formula 6 under metal-catalyzed conditions, as described above for Scheme 2. For a reference illustrating the method of Scheme 3 see, for example, Bioorganic & Medicinal Chemistry Letters 2007, 17, 1189-1192.
Figure imgf000016_0002
As shown in Scheme 4, intermediates of Formula 5 wherein L 2 is Br or I can be prepared by reaction of 5-aminopyrazoles of Formula 3a (i.e. Formula 3 wherein R 5 is H) under diazotization conditions optionally in the presence of copper salts containing bromide or iodide. For example, addition of tert-butyl nitrite to a solution of a 5-aminopyrazole of Formula 3a in the presence of CuBr 2 in a solvent such as acetonitrile provides the corresponding 5-bromopyrazole of Formula 5. Likewise, a 5-aminopyrazole of Formula 3a can be converted to a diazonium salt and then to a corresponding 5-bromo or 5-iodopyrazole of Formula 5 by treatment with sodium nitrite in solvents such as water, acetic acid or trifluoroacetic acid, in the presence of a mineral acid typically containing the same halide atom as L 2 (e.g., aqueous HI solution for L 2 being I), followed by treatment with the corresponding copper(I) or copper(II) salt according to general procedures well-known to those skilled in the art. For a related reference, see J. Comb. Chem.2003, 5, 118-124.
Figure imgf000017_0001
As shown in Scheme 5, compounds of Formula 5 wherein L 2 is Br can also be prepared by reacting pyrazolones of Formula 7 with phosphorus tribromide using the method described in Tetrahedron Lett.2000, 41(24), 4713-4716. Starting pyrazolones of Formula 7 can be prepared by condensation of methyl ketoesters with methyl hydrazine using the method described in Tetrahedron Lett. 2000, 41(24), 4713-4716 and J. Heterocyclic Chem. 1987, 24, 149-153.
Figure imgf000017_0002
7 5
As shown in Scheme 6, compounds of Formula 5 where L 2 is fluoroalkylsulfonyl can be prepared from 5-hydroxypyrazoles of Formula 8 using the method described in Synlett 2004, (5), 795-798. General methods useful for preparing starting compounds of Formula 8 are well-known in the art; for conditions see, for example, Synlett 2004, (5), 795-798 and Chemical & Pharmaceutical Bulletin 1994, 42(8), 1617-1630.
Figure imgf000018_0001
In an alternative method, as shown in Scheme 7, compounds of Formula 1 can be prepared by reaction of 4-bromo or 4-iodo pyrazoles of Formula 9 with organometallic compounds of Formula 10 under transition-metal-catalyzed cross-coupling reaction conditions, in the presence of a suitable palladium, copper or nickel catalyst. In this method compounds of Formula 10 are organoboronic acids (e.g., M1 is B(OH)2), organoboronic esters (e.g., M1 is B(-OC(CH 2 ) 3 O-), organotrifluoroborates (e.g., M1 is BF 3 K), organotin reagents (e.g., M1 is Sn(n-Bu)3, Sn(Me)3), Grignard reagents (e.g., M1 is MgBr or MgCl) or organozinc reagents (e.g., M1 is ZnBr or ZnCl). Suitable metal catalysts include, but are not limited to: palladium(II) acetate, palladium(II) chloride, tetrakis(triphenylphosphine)- palladium(0), bis(triphenylphosphine)palladium(II) dichloride, dichloro[1,1'-bis(diphenyl- phosphino)ferrocene]palladium(II), bis(triphenylphosphine)dichloronickel(II) and copper(I) salts (e.g., copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(I) cyanide or copper(I) triflate). Optimal conditions will depend on the catalyst used and the counterion attached to the coupling reagent (i.e. M1), as is understood by one skilled in the art. In some cases the addition of a ligand such as a substituted phosphine or a substituted bisphosphinoalkane promotes reactivity. Also, the presence of a base such as an alkali carbonate, tertiary amine or alkali fluoride may be necessary for some reactions involving organoboron reagents of the Formula 10. For reviews of this type of reaction see: E. Negishi, Handbook of Organopalladium Chemistry for Organic Synthesis, John Wiley and Sons, Inc., New York, 2002; N. Miyaura, Cross-Coupling Reactions: A Practical Guide, Springer, New York, 2002; H. C. Brown et al., Organic Synthesis via Boranes, Vol. 3, Aldrich Chemical Co., Milwaukee, WI, 2002; Suzuki et al., Chemical Review 1995, 95, 2457-2483 and Molander et al., Accounts of Chemical Research 2007, 40, 275-286. Also, the method of Scheme 7 is illustrated PCT Patent Publications WO 2010/101973 and WO 2012/031061.
Figure imgf000019_0001
General methods useful for preparing 5-aminopyrazole intermediates of Formulae 3 and 3a (shown in the methods of Schemes 2 and 4) are well known in the art; see, for example, Journal für Praktische Chemie (Leipzig) 1911, 83, 171 and J. Am. Chem. Soc. 1954, 76, 501. One such method is illustrated in Scheme 8. Reaction conditions for the method of Scheme 8 are disclosed in PCT Patent Publication WO 2012/031061 Synthesis Example 1, Step A; and Synthesis Example 2, Step C.
Figure imgf000019_0002
As shown in Scheme 9, 5-aminopyrazoles of Formulae 3 and 3a can also be prepared by reacting 4-bromo or 4-iodo pyrazoles of Formula 12 with compounds of Formula 10a (i.e. Formula 10 wherein M1 is B(OH)2) using transition-metal-catalyzed cross-coupling reaction conditions as described in the method of Scheme 7.
Figure imgf000020_0001
As shown in Scheme 10, pyrazole intermediates of Formula 9 (shown in the method of Scheme 7) are readily prepared from corresponding pyrazoles of Formula 13 by treatment with a halogenating agent. Suitable halogenating agents for this method include N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), bromine, sodium bromite, thionyl chloride, oxalyl chloride, phenylphosphonic dichloride or phosgene. Particularly useful is N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS). Suitable solvents for this reaction include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, chlorobutane, benzene, xylenes, chlorobenzene, tetrahydrofuran, p-dioxane, acetonitrile, and the like. Optionally, an organic base such as triethylamine, pyridine, N,N-dimethylaniline, and the like can be added. Typical reaction temperatures range from about ambient temperature to 200 ^C. For representative procedures see Synthesis 2006, 17, 2855-2864; Journal of Medicinal Chemistry 2005, 48, 6843-6854; Journal of Medicinal Chemistry 2007, 50, 3086-3100 and Journal of Medicinal Chemistry 2005, 48, 4420-4431.
Figure imgf000020_0002
As illustrated in Scheme 11, intermediates of Formula 12 can be prepared from compounds of Formula 14 using reaction conditions similar to those described for Scheme 10. Compounds of Formula 14 are commercially available and can be prepared by methods known in the art.
Figure imgf000021_0001
As shown in Scheme 12, compounds of Formula 13 can be prepared from corresponding compounds of Formula 15 by procedures analogous to those used for the method of Scheme 2. Compounds of Formula 15 are commercially available or can be prepared by methods known in the art.
Figure imgf000021_0002
General methods useful for preparing 5-hydroxypyrazole intermediates of Formula 8 (shown in the method of Scheme 6) are well known in the art; see, for example, Annalen der Chemie 1924, 436, 88. One such a method is illustrated in Scheme 13. For reaction conditions for the method of Scheme 13 see, PCT Patent Publication WO 2012/031061, Step C in Synthesis Example 6.
Figure imgf000022_0001
In addition to the methods of Schemes 2 and 3 described above, compounds of Formula 1a (i.e. Formula 1 wherein X is NR 5 ) can also be prepared as shown in Scheme 14. In this method, compounds of Formula 17 are condensed with methylhydrazine in a solvent such as ethanol or methanol and optionally in the presence of an acid or base catalyst such as acetic acid, piperidine or sodium methoxide, according to general procedures known in the art. For reaction conditions see, PCT Patent Publication WO 2013/116251, Step C of Synthesis Example 1 and Step B of Example 2. Also, the method of Scheme 14 using a compound of Formula 17 wherein R b is H is illustrated in Example 1, Step C of the present invention.
Figure imgf000022_0002
Compounds of Formula 2 (shown in the method of Scheme 1) can be prepared by condensing compounds of Formula 17 with hydrazine, in a manner analogous to the method of Scheme 14. This method is described in Chemistry of Heterocyclic Compounds 2005, 41(1), 105–110. As shown in Scheme 15, compounds of Formula 17 wherein, R b is H or lower alkyl can be prepared by reacting the corresponding ketene dithioacetal compounds of Formula 18 with compounds of Formula 6 (wherein R 5 is H) optionally in the presence of a base, such as sodium hydride or ethylmagnesium chloride, in solvents such as toluene, tetrahydrofuran or dimethoxymethane, at temperatures ranging from about–10 °C to the boiling point of the solvent. For a related reference see, for example, J. Heterocycl. Chem. 1975, 12(1), 139. Methods useful for preparing compounds of Formula 18 are known in the art.
Figure imgf000023_0001
As shown in Scheme 16, compounds of Formula 17 wherein R b is lower alkyl (e.g., methyl, ethyl, n-propyl) and Formula 17a (i.e. tautomer of Formula 17 when R b is H) can be prepared via a condensation reaction of corresponding isothiocyanate compounds of Formula 20 with arylacetone compounds of Formula 21 to give intermediate compounds of Formula 22, which are salts of the thioamides of Formula 17a. The intermediate compounds of Formula 22 can either be used in situ (as is illustrated in WO 2013/116251, Synthesis Example 1, Step C) or isolated before further conversion (as is illustrated in WO 2013/116251, Example 2, Step A). Bases useful for preparing compounds of Formula 22 include hydrides, alkoxides, hydroxides or carbonates of sodium or potassium, such as sodium hydride, potassium tert-butoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide or potassium carbonate. Amine bases (e.g., triethylamine or N,N-diisopropyl- ethylamine) can also be used to effect the condensation of the compounds of Formulae 20 and 21 to Formula 22. A variety of solvents are useful, such as tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide, alcohols (e.g., ethanol), esters (e.g., ethyl acetate or isopropyl acetate), or mixtures thereof. Solvents are chosen for compatibility with the base selected, as is well-known in the art. Reaction temperatures can range from–78 °C to the boiling point of the solvent. One useful mixture of base and solvent is potassium tert- butoxide or potassium tert- pentoxide in tetrahydrofuran, to which at–70 to 0 °C is added a solution of an isothiocyanate of Formula 20 and a carbonyl compound of Formula 21, which are either combined into one solution, or added separately, preferably by addition of the carbonyl compound followed by addition of the isothiocyanate. The salt compound of Formula 22 can be acidified to form the ketothioamide compound of Formula 17a or alkylated with R b X 1 (Formula 23) wherein R b is lower alkyl (e.g., methyl, ethyl, n-propyl) and X1 is a nucleofuge (i.e. a nucleophilic reaction leaving group such as Br, I, OS(O) 2 CH 3 ) to form the corresponding compound of Formula 17. This general method is known in the chemical literature; see, for example, Zhurnal Organicheskoi Khimii 1982, 18(12), 2501. Also, the method of Scheme 16 to prepare a compound of Formula 17 wherein R b is methyl from an intermediate compound of Formula 22, which is not isolated, is illustrated in PCT Patent Publication WO 2013/116251 Synthesis Example 1, Step C. Also, the method of Scheme 16 to prepare a compound of Formula 17a is illustrated in Example 1, Step B of the present invention.
Figure imgf000024_0001
Ketothioamides of Formula 17a can also be prepared by allowing the corresponding ketoamides to react with sulfurizing agents such as Lawesson’s reagent or P 2 S 5 ; see, for example, Helv. Chim. Act.1998, 81(7), 1207.
Compounds of Formula 1 and their intermediates described herein can be subjected to various electrophilic, nucleophilic, organometallic, oxidation and reduction reactions to add substituents or modify existing substituents, and thus provide other functionalized compounds of Formula 1. For example, as shown in Scheme 17, compounds of Formula 1 can be prepared by the reaction of the compounds of Formula 24 wherein L 2 leaving group such as a halogen (e.g., Br, I) or sulfonate (e.g., mesylate, triflate, p-toluenesulfonate) with reagents such as 2,4,6-trimethylboroxine, tetramethylstannane or potassium trifluromethyl- borate in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]- palladium(II) chloride dichloromethane adduct, preferably in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate or potassium hydroxide, and in a solvent such as N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, ethanol, toluene or water. This reaction can be carried out in excess alkylating agent (e.g., iodomethane) or using a variety of solvents such as ethers, acetonitrile or N,N-dimethylformamide. The method of Scheme 17 is illustrated PCT Patent Publication WO 2013/192126 Example 4, Step A.
Compounds of Formula 24 can be prepared by methods described in PCT Patent Publications WO 2010/101973 and WO 2012/031061.
Figure imgf000025_0001
Scheme 18 illustrates another example where compounds of Formula 1a wherein R 5 is other than H can be prepared from the corresponding compounds of Formula 1a wherein R 5 is H by reaction with an electrophile comprising R 5 (i.e. Formula 25). Typically the reaction is done in the presence of a base such as sodium hydride and a polar solvent such as N,N- dimethylformamide. In this context the expression“electrophile comprising R 5 ” means a chemical compound capable of transferring an R 5 moiety to a nucleophile (such as the nitrogen atom in Formula 1a when R 5 is H). Often electrophiles comprising R 5 have the formula R 5 X 1 wherein X 1 is a nucleofuge (i.e. leaving group in nucleophilic reactions). Typical nucleofuges include halide (e.g., Br, Cl, I) or sulfonate (e.g., mesylate, triflate, p- toluenesulfonate). However, some electrophiles comprising R 5 do not comprise a nucleofuge; an example is sulfur trioxide (SO 3 ), which after deprotonation (such as by a base of the formulae M + H – wherein M + is a cation) of the nitrogen atom in Formula 1a, can bond to the nitrogen atom as a -SO 3 M substituent.
Figure imgf000026_0001
Compounds of Formula 1b (i.e. Formula 1 where in X is CR 6 OR 7 ) wherein R 6 and R 7 are H can be prepared as shown in Scheme 19. In this method compounds of Formula 26 are first treated with organometallic reagents of Formula 27 such as alkyl lithium base (e.g., n-butyllithium, s-butyllithium or lithium diisopropylamide) or Grignard reagents in a solvent such as toluene, diethyl ether, tetrahydrofuran or dimethoxymethane at temperatures ranging from about–78 °C to ambient temperature. The resulting anions are then contacted with aldehydes of Formula 28 to provide compounds Formula 1b. There are a wide-variety of general methods described in the synthetic literature for metalation/alkylation reactions which can be readily adapted to prepare compounds of the present invention; see, for example, J. Org. Chem.2010, 75, 984-987.
Aldehydes of Formula 28 are commercially available and can be prepared by methods known in the art. Compounds of Formula 26 are known and can be prepared by methods analogous to those disclosed in Schemes 4 and 5, and by a variety of methods disclosed in the chemical literature.
Figure imgf000027_0001
As shown in Scheme 20, compounds of Formula 1b wherein R 6 is alkyl can be prepared by reacting compounds of Formula 29 with alkylmagnesium halide. Typically the reaction is run in the presence of zinc chloride and in a solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from about 0 to 100 °C (for references see, for example, Organic Lett.2009, 11, 1659-1662 and J. Am. Chem. Soc.2006, 128, 9998-9999).
Figure imgf000027_0002
As shown in Scheme 21, compounds of Formula 29 can be prepared by contacting compounds of Formula 30 with acid chlorides of Formula 31 in the presence of a Lewis acid (e.g., aluminum chloride, boron trifluoride diethyl etherate or tin tetrachloride) in a solvent such as dichloromethane, tetrachloroethane or nitrobenzene, at temperatures ranging from about 0 to 200 °C.
Figure imgf000028_0001
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme above, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1. One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1 H NMR spectra are reported in ppm downfield from tetramethylsilane in CDCl 3 unless otherwise noted;“s” means singlet,“d” means doublet, and“m” means multiplet.
EXAMPLE 1
Preparation of 4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4- yl]-3-chlorobenzonitrile (Compound 11)
Step A: Preparation of 3-chloro-4-(2-oxopropyl)benzonitrile
Concentrated sulfuric acid (5.30 g) was added dropwise over 5 minutes to a solution of water (100 mL) while maintaining the reaction temperature below 10 °C. After the addition was complete, the reaction mixture was cooled to about 0 to 5 °C, and then 4-amino-3- chlorobenzonitrile (3.81 g, 25 mmol) was added, followed by sodium nitrite (5.0 g, 29 mmol) in water (12.5 g). The reaction mixture was stirred for 3 h while maintaining the temperature at about 0 to 5 °C, after which time isopropenyl acetate (20.0 g, 200 mmol) was added, followed by a solution of copper(II) sulfate pentahydrate (0.34 g, 1.4 mmol) in water (5 mL). After stirring for 5 minutes, a solution of sodium sulfite (1.6 g) in water (40 mL) was added to the reaction mixture while maintaining the reaction temperature between about 10 to 20 °C. The reaction mixture was allowed to warm to room temperature and stirred for about 24 h. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography through silica gel (eluting with a gradient of ethyl acetate/hexanes 0:100 to 30:70) to provide the title compound as a solid (2.96 g).
1H NMR (CDCl3): ^ 7.69 (d, 1H), 7.54 (m, 1H), 7.33 (d, 1H), 3.93 (s, 2H), 2.28 (s, 3H). Step B: Preparation of ^-acetyl-N-(2-bromo-6-fluoro-4-methylphenyl)-2-chloro-4- cyanobenzeneethanethioamide (tautomer of 4-[1-[[(2-bromo-6-fluoro-4- methylphenyl)amino]mercaptomethylene]-2-oxoproply]-3-chlorobenzonitrile) Potassium tert-pentoxide (1.7 M in toluene, 1.57 mL, 2.58 mmol) was added to a solution of tetrahydrofuran (12 mL). The reaction mixture was cooled to about–10 °C, and then a mixture of 3-chloro-4-(2-oxopropyl)benzonitrile (i.e. the product of Step A) (0.50 g, 2.58 mmol) and 1-bromo-3-fluoro-2-isothiocyanato-5-methylbenzene (0.58 g, 2.35 mmol) in toluene (5 mL) was added dropwise while maintaining the reaction temperature below 5 °C. The reaction mixture was stirred for 10 minutes at about–10 °C, and then hydrochloric acid (1 N aqueous solution, 2.94 mL) was added dropwise while maintaining the temperature below 5 °C. The reaction mixture was allowed to warm to room temperature, and diluted with ethyl acetate and water. The organic layer was separated and washed with saturated sodium chloride, dried over magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure to provide the title compound (1.0 g), which was used without further purification. Step C: Preparation of 4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl- 1H-pyrazol-4-yl]-3-chlorobenzonitrile
To a mixture of ^-acetyl-N-(2-bromo-6-fluoro-4-methylphenyl)-2-chloro-4-cyano- benzeneethanethioamide (i.e. the product of Step B) (1.0 g) in methanol (6.5 mL) was added water (0.22 mL) and glacial acetic acid (0.61 g, 10.22 mmol), followed by methylhydrazine (0.33 g, 6.87 mmol). The reaction mixture was heated at reflux for 2.5 h, and then allowed to come to room temperature. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography through silica gel (eluting with a gradient of ethyl acetate/hexanes 0:100 to 40:60). The resulting material was triturated in a mixture of ethyl acetate, hexanes and n-butyl chloride to provide the title, a compound of the present invention, as a solid (0.25 g).
1H NMR (CDCl3): ^ 7.59 (d, 1H), 7.39 (m, 1H), 7.21 (d, 1H), 6.95 (s, 1H), 6.61 (m, 1H), 5.35 (s, 1H), 3.77 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H).
As described for Schemes 14 and 16, compounds of Formula 17 including Formula 17a (tautomer of Formula 17 when R b is H) are useful process intermediates for preparing compounds of Formula 1. Illustrative of compounds of Formulae 17 and 17a are those specifically disclosed in Table 1a and 1b below. Also, an example of a compound of Formula 17a is specifically disclosed as the product in Step B of Example 1.
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000031_0002
Figure imgf000031_0001
Cl Cl Cl H Br F Cl H Br F Br H Cl Cl F H As described for Scheme 16, compounds of Formula 22 are salts of the thioamides of Formula 17a. Illustrative of compounds of Formula 22 are those specifically disclosed in Table 2 below.
Figure imgf000032_0001
As described for Scheme 16, compounds of Formula 20 are useful process intermediates for preparing compounds of Formulae 17 and 17a, which in turn are useful intermediates for preparing compounds of Formula 1. An example of a compound of Formula 20 is specifically disclosed in Step B of Example 1. Additional examples are found in Table 3 below. TABLE 3
Figure imgf000033_0001
R1 R 2 R 1 R 2 Cl Cl Br Cl Br F Cl H Cl F Br H F F F H
As described for Scheme 3, compounds of Formula 6 are useful process intermediates for preparing compounds of Formula 1. Additionally, compounds of Formula 6 (when R 5 is H) are useful process intermediates for preparing compounds of Formula 17 (as shown in Scheme 15), which in turn are useful intermediates for preparing compounds of Formula 1. An example of a compound of Formula 6 (when R 5 is H) is specifically disclosed in Step A of Example 1. Additional examples are found in Table 4 below.
TABLE 4
Figure imgf000033_0002
R1 R 2 R 1 R 2 F H Cl F Cl H Br F Br H Cl Cl F F
Formulation/Utility
A compound of this invention will generally be used as a fungicidal active ingredient in a composition, i.e. formulation, with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents, which serve as a carrier. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful formulations include both liquid and solid compositions. Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like, which optionally can be thickened into gels. The general types of aqueous liquid compositions are soluble concentrate, suspension concentrate, capsule suspension, concentrated emulsion, microemulsion and suspo-emulsion. The general types of nonaqueous liquid compositions are emulsifiable concentrate, microemulsifiable concentrate, dispersible concentrate and oil dispersion.
The general types of solid compositions are dusts, powders, granules, pellets, prills, pastilles, tablets, filled films (including seed coatings) and the like, which can be water-dispersible (“wettable”) or water-soluble. Films and coatings formed from film- forming solutions or flowable suspensions are particularly useful for seed treatment. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or “overcoated”). Encapsulation can control or delay release of the active ingredient. An emulsifiable granule combines the advantages of both an emulsifiable concentrate formulation and a dry granular formulation. High-strength compositions are primarily used as intermediates for further formulation.
Sprayable formulations are typically extended in a suitable medium before spraying. Such liquid and solid formulations are formulated to be readily diluted in the spray medium, usually water. Spray volumes can range from about one to several thousand liters per hectare, but more typically are in the range from about ten to several hundred liters per hectare. Sprayable formulations can be tank mixed with water or another suitable medium for foliar treatment by aerial or ground application, or for application to the growing medium of the plant. Liquid and dry formulations can be metered directly into drip irrigation systems or metered into the furrow during planting. Liquid and solid formulations can be applied onto seeds of crops and other desirable vegetation as seed treatments before planting to protect developing roots and other subterranean plant parts and/or foliage through systemic uptake.
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
Figure imgf000034_0001
Figure imgf000035_0001
Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey.
Liquid diluents include, for example, water, N,N-dimethylalkanamides (e.g., N,N- dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N- methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate, sorbitol, aromatic hydrocarbons, dearomatized aliphatics, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy- 4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate and isobornyl acetate, other esters such as alkylated lactate esters, dibasic esters and γ-butyrolactone, and alcohols, which can be linear, branched, saturated or unsaturated, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol. Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C 6 -C 22 ), such as plant seed and fruit oils (e.g., oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower, grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palm kernel), animal-sourced fats (e.g., beef tallow, pork tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g., methylated, ethylated, butylated) wherein the fatty acids may be obtained by hydrolysis of glycerol esters from plant and animal sources, and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950.
The solid and liquid compositions of the present invention often include one or more surfactants. When added to a liquid, surfactants (also known as“surface-active agents”) generally modify, most often reduce, the surface tension of the liquid. Depending on the nature of the hydrophilic and lipophilic groups in a surfactant molecule, surfactants can be useful as wetting agents, dispersants, emulsifiers or defoaming agents.
Surfactants can be classified as nonionic, anionic or cationic. Nonionic surfactants useful for the present compositions include, but are not limited to: alcohol alkoxylates such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and prepared from the alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides such as ethoxylated soybean, castor and rapeseed oils; alkylphenol alkoxylates such as octylphenol ethoxylates, nonylphenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (prepared from the phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers prepared from ethylene oxide or propylene oxide and reverse block polymers where the terminal blocks are prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenol (including those prepared from ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); fatty acid esters, glycerol esters, lanolin-based derivatives, polyethoxylate esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd peg (polyethylene glycol) resins, graft or comb polymers and star polymers; polyethylene glycols (pegs); polyethylene glycol fatty acid esters; silicone-based surfactants; and sugar-derivatives such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides.
Useful anionic surfactants include, but are not limited to: alkylaryl sulfonic acids and their salts; carboxylated alcohol or alkylphenol ethoxylates; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates and phosphate esters of styryl phenol ethoxylates; protein-based surfactants; sarcosine derivatives; styryl phenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; sulfonates of amines and amides such as N,N-alkyltaurates; sulfonates of benzene, cumene, toluene, xylene, and dodecyl and tridecylbenzenes; sulfonates of condensed naphthalenes; sulfonates of naphthalene and alkyl naphthalene; sulfonates of fractionated petroleum; sulfosuccinamates; and sulfosuccinates and their derivatives such as dialkyl sulfosuccinate salts.
Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propanediamines, tripropylenetriamines and dipropylenetetramines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (prepared from the amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxides and bis-(2-hydroxyethyl)-alkylamine oxides.
Also useful for the present compositions are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published references including McCutcheon’s Emulsifiers and Detergents, annual American and International Editions published by McCutcheon’s Division, The Manufacturing Confectioner Publishing Co.; Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964; and A. S. Davidson and B. Milwidsky, Synthetic Detergents, Seventh Edition, John Wiley and Sons, New York, 1987.
Compositions of this invention may also contain formulation auxiliaries and additives, known to those skilled in the art as formulation aids (some of which may be considered to also function as solid diluents, liquid diluents or surfactants). Such formulation auxiliaries and additives may control: pH (buffers), foaming during processing (antifoams such polyorganosiloxanes), sedimentation of active ingredients (suspending agents), viscosity (thixotropic thickeners), in-container microbial growth (antimicrobials), product freezing (antifreezes), color (dyes/pigment dispersions), wash-off (film formers or stickers), evaporation (evaporation retardants), and other formulation attributes. Film formers include, for example, polyvinyl acetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers and waxes. Examples of formulation auxiliaries and additives include those listed in McCutcheon’s Volume 2: Functional Materials, annual International and North American editions published by McCutcheon’s Division, The Manufacturing Confectioner Publishing Co.; and PCT Publication WO 03/024222.
The compound of Formula 1 and any other active ingredients are typically incorporated into the present compositions by dissolving the active ingredient in a solvent or by grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of a liquid composition intended for use as an emulsifiable concentrate is water-immiscible, an emulsifier is typically added to emulsify the active-containing solvent upon dilution with water. Active ingredient slurries, with particle diameters of up to 2,000 μm can be wet milled using media mills to obtain particles with average diameters below 3 μm. Aqueous slurries can be made into finished suspension concentrates (see, for example, U.S. 3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations usually require dry milling processes, which produce average particle diameters in the 2 to 10 μm range. Dusts and powders can be prepared by blending and usually grinding (such as with a hammer mill or fluid-energy mill). Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, “Agglomeration”, Chemical Engineering, December 4, 1967, pp 147-48, Perry’s Chemical Engineer’s Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S.4,172,714. Water- dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
For further information regarding the art of formulation, see T. S. Woods,“The Formulator’s Toolbox - Product Forms for Modern Agriculture” in Pesticide Chemistry and Bioscience, The Food-Environment Challenge, T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp.120-133. See also U.S.3,235,361, Col.6, line 16 through Col.7, line 19 and Examples 10-41; U.S.3,309,192, Col.5, line 43 through Col.7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S.2,891,855, Col.3, line 66 through Col.5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology, PJB Publications, Richmond, UK, 2000.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Table A. Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be constructed as merely illustrative, and not limiting of the disclosure in any way whatsoever.
Example A
High Strength Concentrate
Compound 1 98.5% silica aerogel 0.5% synthetic amorphous fine silica 1.0% Example B
Wettable Powder
Compound 5 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%
Example C
Granule
Compound 8 10.0% attapulgite granules (low volatile matter, 0.71/0.30 mm; 90.0% U.S.S. No.25–50 sieves)
Example D
Extruded Pellet
Compound 9 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%
Example E
Emulsifiable Concentrate
Compound 11 10.0% polyoxyethylene sorbitol hexoleate 20.0% C6 –C 10 fatty acid methyl ester 70.0%
Example F
Microemulsion
Compound 12 5.0% polyvinylpyrrolidone-vinyl acetate copolymer 30.0% alkylpolyglycoside 30.0% glyceryl monooleate 15.0% water 20.0%
Example G
Seed Treatment
Compound 6 20.00% polyvinylpyrrolidone-vinyl acetate copolymer 5.00% montan acid wax 5.00% calcium ligninsulfonate 1.00% polyoxyethylene/polyoxypropylene block copolymers 1.00% stearyl alcohol (POE 20) 2.00% polyorganosilane 0.20% colorant red dye 0.05% water 65.75% Water-soluble and water-dispersible formulations are typically diluted with water to form aqueous compositions before application. Aqueous compositions for direct applications to the plant or portion thereof (e.g., spray tank compositions) typically contain at least about 1 ppm or more (e.g., from 1 ppm to 100 ppm) of the compound(s) of this invention.
The compounds of this invention are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound. The compounds and/or compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, turf, vegetable, field, cereal, and fruit crops. These pathogens include: Oomycetes, including Phytophthora diseases such as Phytophthora infestans, Phytophthora megasperma, Phytophthora parasitica, Phytophthora cinnamomi and Phytophthora capsici, Pythium diseases such as Pythium aphanidermatum, and diseases in the Peronosporaceae family such as Plasmopara viticola, Peronospora spp. (including Peronospora tabacina and Peronospora parasitica), Pseudoperonospora spp. (including Pseudoperonospora cubensis) and Bremia lactucae; Ascomycetes, including Alternaria diseases such as Alternaria solani and Alternaria brassicae, Guignardia diseases such as Guignardia bidwell, Venturia diseases such as Venturia inaequalis, Septoria diseases such as Septoria nodorum and Septoria tritici, powdery mildew diseases such as Erysiphe spp. (including Erysiphe graminis and Erysiphe polygoni), Uncinula necatur, Sphaerotheca fuliginea, Podosphaera leucotricha and Pseudocercosporella herpotrichoides, Botrytis diseases such as Botrytis cinerea, Monilinia fructicola, Sclerotinia diseases such as Sclerotinia sclerotiorum, Sclerotinia minor, Magnaporthe grisea, and Phomopsis viticola, Helminthosporium diseases such as Helminthosporium tritici repentis and Pyrenophora teres, anthracnose diseases such as Glomerella or Colletotrichum spp. (such as Colletotrichum graminicola and Colletotrichum orbiculare), and Gaeumannomyces graminis; Basidiomycetes, including rust diseases caused by Puccinia spp. (such as Puccinia recondita, Puccinia striiformis, Puccinia hordei, Puccinia graminis and Puccinia arachidis), Hemileia vastatrix and Phakopsora pachyrhizi; other pathogens including Rutstroemia floccosum (also known as Sclerotinia homoeocarpa); Rhizoctonia spp. (such as Rhizoctonia solani); Fusarium diseases such as Fusarium roseum, Fusarium graminearum and Fusarium oxysporumVerticillium dahliae; Sclerotium rolfsii; Rynchosporium secalis; Cercosporidium personatum, Cercospora arachidicola and Cercospora beticola; Rhizopus spp. (such as Rhizopus stolonifer); Aspergillus spp. (such as Aspergillus flavus and Aspergillus parasiticus); and other genera and species closely related to these pathogens. In addition to their fungicidal activity, the compositions or combinations also have activity against bacteria such as Erwinia amylovora, Xanthomonas campestris, Pseudomonas syringae, and other related species. Furthermore, the compounds of this invention are useful in treating postharvest diseases of fruits and vegetables caused by fungi and bacteria. These infections can occur before, during and after harvest. For example, infections can occur before harvest and then remain dormant until some point during ripening (e.g., host begins tissue changes in such a way that infection can progress); also infections can arise from surface wounds created by mechanical or insect injury. In this respect, the compounds of this invention can reduce losses (i.e. losses resulting from quantity and quality) due to postharvest diseases which may occur at any time from harvest to consumption. Treatment of postharvest diseases with compounds of the invention can increase the period of time during which perishable edible plant parts (e.g, fruits, seeds, foliage, stems, bulbs, tubers) can be stored refrigerated or un-refrigerated after harvest, and remain edible and free from noticeable or harmful degradation or contamination by fungi or other microorganisms. Treatment of edible plant parts before or after harvest with compounds of the invention can also decrease the formation of toxic metabolites of fungi or other microorganisms, for example, mycotoxins such as aflatoxins.
Remarkably, pyrazole compounds of Formula 1 with both a 4-methyl-anilino group as well as a 4-CN-phenyl group have now been discovered to have significantly improved control of certain plant diseases compared to corresponding compounds wherein the aniline ring and the phenyl ring have a hydrogen or halogen (i.e. F, Cl or Br) substituent at the 4- position. In particular, compounds of Formula 1 compared to para-halo substituted analogs or analogs with a hydrogen at the para position have been found to provide surprisingly improved antifungal activity against plant fungal diseases, such as Septoria tritici. Because of their extraordinarily desirable biological profile, compounds of Formula 1 are remarkably useful as fungicides alone and in combination with other biologically active compounds or agents. Moreover, process intermediates useful for preparing compounds of Formula 1, such as compounds of Formulae 17, 20 and 22 are correspondingly particularly useful.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruits, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to seeds to protect the seeds and seedlings developing from the seeds. The compounds can also be applied through irrigation water to treat plants. Control of postharvest pathogens which infect the produce before harvest is typically accomplished by field application of a compound of this invention, and in cases where infection occurs after harvest the compounds can be applied to the harvested crop as dips, sprays, fumigants, treated wraps and box liners. Rates of application for these compounds (i.e. a fungicidally effective amount) can be influenced by factors such as the plant diseases to be controlled, the plant species to be protected, ambient moisture and temperature and should be determined under actual use conditions. One skilled in the art can easily determine through simple experimentation the fungicidally effective amount necessary for the desired level of plant disease control. Foliage can normally be protected when treated at a rate of from less than about 1 g/ha to about 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from about 0.1 to about 10 g per kilogram of seed.
Compounds of this invention can also be mixed with one or more other biologically active compounds or agents including fungicides, insecticides, nematocides, bactericides, acaricides, herbicides, herbicide safeners, growth regulators such as insect molting inhibitors and rooting stimulants, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants, plant nutrients, other biologically active compounds or entomopathogenic bacteria, virus or fungi to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Thus the present invention also pertains to a composition comprising a compound of Formula 1 (in a fungicidally effective amount) and at least one additional biologically active compound or agent (in a biologically effective amount) and can further comprise at least one of a surfactant, a solid diluent or a liquid diluent. The other biologically active compounds or agents can be formulated in compositions comprising at least one of a surfactant, solid or liquid diluent. For mixtures of the present invention, one or more other biologically active compounds or agents can be formulated together with a compound of Formula 1, to form a premix, or one or more other biologically active compounds or agents can be formulated separately from the compound of Formula 1, and the formulations combined together before application (e.g., in a spray tank) or, alternatively, applied in succession.
As mentioned in the Summary of the Invention, one aspect of the present invention is a fungicidal composition comprising (i.e. a mixture or combination of) a compound of Formula 1, an N-oxide, or a salt thereof (which is identified as component (a)), and at least one other fungicide (which is identified as component (b)).
Of note is a composition which, in addition to the Formula 1 compound of component (a), includes as component (b) at least one fungicidal compound selected from the group consisting of the classes (b1) methyl benzimidazole carbamate (MBC) fungicides; (b2) dicarboximide fungicides; (b3) demethylation inhibitor (DMI) fungicides; (b4) phenylamide fungicides; (b5) amine/morpholine fungicides; (b6) phospholipid biosynthesis inhibitor fungicides; (b7) carboxamide fungicides; (b8) hydroxy(2-amino)pyrimidine fungicides; (b9) anilinopyrimidine fungicides; (b10) N-phenyl carbamate fungicides; (b11) quinone outside inhibitor (QoI) fungicides; (b12) phenylpyrrole fungicides; (b13) quinoline fungicides; (b14) lipid peroxidation inhibitor fungicides; (b15) melanin biosynthesis inhibitors-reductase (MBI-R) fungicides; (b16) melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides; (b17) hydroxyanilide fungicides; (b18) squalene-epoxidase inhibitor fungicides; (b19) polyoxin fungicides; (b20) phenylurea fungicides; (b21) quinone inside inhibitor (QiI) fungicides; (b22) benzamide fungicides; (b23) enopyranuronic acid antibiotic fungicides; (b24) hexopyranosyl antibiotic fungicides; (b25) glucopyranosyl antibiotic: protein synthesis fungicides; (b26) glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides; (b27) cyanoacetamideoxime fungicides; (b28) carbamate fungicides; (b29) oxidative phosphorylation uncoupling fungicides; (b30) organo tin fungicides; (b31) carboxylic acid fungicides; (b32) heteroaromatic fungicides; (b33) phosphonate fungicides; (b34) phthalamic acid fungicides; (b35) benzotriazine fungicides; (b36) benzene-sulfonamide fungicides; (b37) pyridazinone fungicides; (b38) thiophene-carboxamide fungicides; (b39) pyrimidinamide fungicides; (b40) carboxylic acid amide (CAA) fungicides; (b41) tetracycline antibiotic fungicides; (b42) thiocarbamate fungicides; (b43) benzamide fungicides; (b44) host plant defense induction fungicides; (b45) multi-site contact activity fungicides; (b46) fungicides other than classes (b1) through (b45); and salts of compounds of classes (b1) through (b46).
Further descriptions of these classes of fungicidal compounds are provided below. (b1)“Methyl benzimidazole carbamate (MBC) fungicides” (Fungicide Resistance Action Committee (FRAC) code 1) inhibit mitosis by binding to β-tubulin during microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Methyl benzimidazole carbamate fungicides include benzimidazoles and thiophanates. The benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole. The thiophanates include thiophanate and thiophanate-methyl.
(b2)“Dicarboximide fungicides” (Fungicide Resistance Action Committee (FRAC) code 2) are proposed to inhibit a lipid peroxidation in fungi through interference with NADH cytochrome c reductase. Examples include chlozolinate, iprodione, procymidone and vinclozolin.
(b3) “Demethylation inhibitor (DMI) fungicides” (Fungicide Resistance Action Committee (FRAC) code 3) inhibit C14-demethylase, which plays a role in sterol production. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Demethylation fungicides include piperazines, pyridines, pyrimidines, imidazoles and triazoles. The piperazines include triforine. The pyridines include buthiobate and pyrifenox. The pyrimidines include fenarimol, nuarimol and triarimol. The imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole. The triazoles include azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, 1-[[(2S,3R)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H- 1,2,4-triazole, 2-[[(2S,3R)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)-2-oxiranyl]methyl]- 1,2-dihydro-3H-1,2,4-triazole-3-thione and 1-[[(2S,3R)-3-(2-chlorophenyl)-2-(2,4-difluoro- phenyl)-2-oxiranyl]methyl]-5-(2-propen-1-ylthio)-1H-1,2,4-triazole. The imidazoles include clotrimazole, imazalil, oxpoconazole, prochloraz, pefurazoate and triflumizole. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205–258.
(b4)“Phenylamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 4) are specific inhibitors of RNA polymerase in Oomycete fungi. Sensitive fungi exposed to these fungicides show a reduced capacity to incorporate uridine into rRNA. Growth and development in sensitive fungi is prevented by exposure to this class of fungicide. Phenylamide fungicides include acylalanines, oxazolidinones and butyrolactones. The acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl and metalaxyl- M/mefenoxam. The oxazolidinones include oxadixyl. The butyrolactones include ofurace.
(b5) “Amine/morpholine fungicides” (Fungicide Resistance Action Committee (FRAC) code 5) inhibit two target sites within the sterol biosynthetic pathway, Δ 8 → Δ 7 isomerase and Δ 14 reductase. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore, exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Amine/morpholine fungicides (also known as non-DMI sterol biosynthesis inhibitors) include morpholines, piperidines and spiroketal-amines. The morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin and piperalin. The spiroketal-amines include spiroxamine.
(b6)“Phospholipid biosynthesis inhibitor fungicides” (Fungicide Resistance Action Committee (FRAC) code 6) inhibit growth of fungi by affecting phospholipid biosynthesis. Phospholipid biosynthesis fungicides include phophorothiolates and dithiolanes. The phosphorothiolates include edifenphos, iprobenfos and pyrazophos. The dithiolanes include isoprothiolane.
(b7)“Carboxamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 7) inhibit Complex II (succinate dehydrogenase) fungal respiration by disrupting a key enzyme in the Krebs Cycle (TCA cycle) named succinate dehydrogenase. Inhibiting respiration prevents the fungus from making ATP, and thus inhibits growth and reproduction. Carboxamide fungicides include phenyl benzamides, pyridinyl ethyl benzamides, furan carboxamides, oxathiin carboxamides, thiazole carboxamides, pyrazole carboxamides and pyridine carboxamides. The phenyl benzamides include benodanil, flutolanil and mepronil. The pyridinyl ethyl benzamides include fluopyram. The furan carboxamides include fenfuram. The oxathiin carboxamides include carboxin and oxycarboxin. The thiazole carboxamides include thifluzamide. The pyrazole carboxamides include furametpyr, penthiopyrad, bixafen, isopyrazam, benzovindiflupyr, N-[2-(1S,2R)- [1,1'-bicyclopropyl]-2-ylphenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, penflufen, (N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbox- amide), N-[2-(2,4-dichlorophenyl)-2-methoxy-1-methylethyl]-3-(difluoromethyl)-1-methyl- 1H-pyrazole-4-carboxamide and N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[[2- (1-methylethyl)phenyl]methyl]-1H-pyrazole-4-carboxamide. The pyridine carboxamides include boscalid.
(b8) “Hydroxy(2-amino-)pyrimidine fungicides” (Fungicide Resistance Action Committee (FRAC) code 8) inhibit nucleic acid synthesis by interfering with adenosine deaminase. Examples include bupirimate, dimethirimol and ethirimol.
(b9)“Anilinopyrimidine fungicides” (Fungicide Resistance Action Committee (FRAC) code 9) are proposed to inhibit biosynthesis of the amino acid methionine and to disrupt the secretion of hydrolytic enzymes that lyse plant cells during infection. Examples include cyprodinil, mepanipyrim and pyrimethanil.
(b10)“N-Phenyl carbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code 10) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include diethofencarb.
(b11)“Quinone outside inhibitor (QoI) fungicides” (Fungicide Resistance Action Committee (FRAC) code 11) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol oxidase. Oxidation of ubiquinol is blocked at the“quinone outside” (Q o ) site of the cytochrome bc 1 complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone outside inhibitor fungicides (also known as strobilurin fungicides) include methoxyacrylates, methoxycarbamates, oximinoacetates, oximinoacetamides, oxazolidinediones, dihydrodioxazines, imidazolinones and benzylcarbamates. The methoxyacrylates include azoxystrobin, coumoxystrobin, enestroburin, flufenoxystrobin, picoxystrobin and pyraoxystrobin. The methoxycarbamates include pyraclostrobin, pyrametostrobin and triclopyricarb. The oximinoacetates include kresoxim-methyl and trifloxystrobin. The oximinoacetamides include dimoxystrobin, metominostrobin, orysastrobin, α-[methoxyimino]-N-methyl-2-[[[1-[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyl]benzeneacetamide and 2-[[[3-(2,6-dichlorophenyl)-1-methyl-2-propen-1-ylidene]- amino]oxy]methyl]-α-(methoxyimino)-N-methylbenzeneacetamide. The oxazolidinediones include famoxadone. The dihydrodioxazines include fluoxastrobin. The imidazolinones include fenamidone. The benzylcarbamates include pyribencarb. Class (11) also includes 2- [(2,5-dimethylphenoxy)methyl]- ^-methoxy-N-benzeneacetamide.
(b12)“Phenylpyrrole fungicides” (Fungicide Resistance Action Committee (FRAC) code 12) inhibit a MAP protein kinase associated with osmotic signal transduction in fungi. Fenpiclonil and fludioxonil are examples of this fungicide class.
(b13)“Azanaphthalene fungicides” (Fungicide Resistance Action Committee (FRAC) code 13) are proposed to inhibit signal transduction by affecting G-proteins in early cell signaling. They have been shown to interfere with germination and/or appressorium formation in fungi that cause powder mildew diseases. Azanaphthalene fungicides include aryloxyquinolines and quinazolinone. The aryloxyquinolines include quinoxyfen and tebufloquin. The quinazolinones include proquinazid.
(b14) “Lipid peroxidation inhibitor fungicides” (Fungicide Resistance Action Committee (FRAC) code 14) are proposed to inhibit lipid peroxidation which affects membrane synthesis in fungi. Members of this class, such as etridiazole, may also affect other biological processes such as respiration and melanin biosynthesis. Lipid peroxidation fungicides include aromatic carbons and 1,2,4-thiadiazoles. The aromatic carbon fungicides include biphenyl, chloroneb, dicloran, quintozene, tecnazene and tolclofos-methyl. The 1,2,4-thiadiazole fungicides include etridiazole.
(b15)“Melanin biosynthesis inhibitors-reductase (MBI-R) fungicides” (Fungicide Resistance Action Committee (FRAC) code 16.1) inhibit the naphthal reduction step in melanin biosynthesis. Melanin is required for host plant infection by some fungi. Melanin biosynthesis inhibitors-reductase fungicides include isobenzofuranones, pyrroloquinolinones and triazolobenzothiazoles. The isobenzofuranones include fthalide. The pyrroloquinolinones include pyroquilon. The triazolobenzothiazoles include tricyclazole.
(b16)“Melanin biosynthesis inhibitors-dehydratase (MBI-D) fungicides” (Fungicide Resistance Action Committee (FRAC) code 16.2) inhibit scytalone dehydratase in melanin biosynthesis. Melanin in required for host plant infection by some fungi. Melanin biosynthesis inhibitors-dehydratase fungicides include cyclopropanecarboxamides, carboxamides and propionamides. The cyclopropanecarboxamides include carpropamid. The carboxamides include diclocymet. The propionamides include fenoxanil.
(b17)“Hydroxyanilide fungicides (Fungicide Resistance Action Committee (FRAC) code 17) inhibit C4-demethylase which plays a role in sterol production. Examples include fenhexamid.
(b18) “Squalene-epoxidase inhibitor fungicides” (Fungicide Resistance Action Committee (FRAC) code 18) inhibit squalene-epoxidase in ergosterol biosynthesis pathway. Sterols such as ergosterol are needed for membrane structure and function, making them essential for the development of functional cell walls. Therefore exposure to these fungicides results in abnormal growth and eventually death of sensitive fungi. Squalene- epoxidase inhibitor fungicides include thiocarbamates and allylaminess. The thiocarbamates include pyributicarb. The allylamines include naftifine and terbinafine.
(b19)“Polyoxin fungicides” (Fungicide Resistance Action Committee (FRAC) code 19) inhibit chitin synthase. Examples include polyoxin.
(b20)“Phenylurea fungicides” (Fungicide Resistance Action Committee (FRAC) code 20) are proposed to affect cell division. Examples include pencycuron.
(b21)“Quinone inside inhibitor (QiI) fungicides” (Fungicide Resistance Action Committee (FRAC) code 21) inhibit Complex III mitochondrial respiration in fungi by affecting ubiquinol reductase. Reduction of ubiquinol is blocked at the“quinone inside” (Q i ) site of the cytochrome bc 1 complex, which is located in the inner mitochondrial membrane of fungi. Inhibiting mitochondrial respiration prevents normal fungal growth and development. Quinone inside inhibitor fungicides include cyanoimidazoles and sulfamoyltriazoles. The cyanoimidazoles include cyazofamid. The sulfamoyltriazoles include amisulbrom.
(b22)“Benzamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 22) inhibit mitosis by binding to β-tubulin and disrupting microtubule assembly. Inhibition of microtubule assembly can disrupt cell division, transport within the cell and cell structure. Examples include zoxamide.
(b23)“Enopyranuronic acid antibiotic fungicides” (Fungicide Resistance Action Committee (FRAC) code 23) inhibit growth of fungi by affecting protein biosynthesis. Examples include blasticidin-S.
(b24)“Hexopyranosyl antibiotic fungicides” (Fungicide Resistance Action Committee (FRAC) code 24) inhibit growth of fungi by affecting protein biosynthesis. Examples include kasugamycin.
(b25)“Glucopyranosyl antibiotic: protein synthesis fungicides” (Fungicide Resistance Action Committee (FRAC) code 25) inhibit growth of fungi by affecting protein biosynthesis. Examples include streptomycin.
(b26)“Glucopyranosyl antibiotic: trehalase and inositol biosynthesis fungicides” (Fungicide Resistance Action Committee (FRAC) code 26) inhibit trehalase in inositol biosynthesis pathway. Examples include validamycin.
(b27)“Cyanoacetamideoxime fungicides (Fungicide Resistance Action Committee (FRAC) code 27) include cymoxanil.
(b28)“Carbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code 28) are considered multi-site inhibitors of fungal growth. They are proposed to interfere with the synthesis of fatty acids in cell membranes, which then disrupts cell membrane permeability. Propamacarb, propamacarb-hydrochloride, iodocarb, and prothiocarb are examples of this fungicide class. (b29)“Oxidative phosphorylation uncoupling fungicides” (Fungicide Resistance Action Committee (FRAC) code 29) inhibit fungal respiration by uncoupling oxidative phosphorylation. Inhibiting respiration prevents normal fungal growth and development. This class includes 2,6-dinitroanilines such as fluazinam, pyrimidonehydrazones such as ferimzone and dinitrophenyl crotonates such as dinocap, meptyldinocap and binapacryl.
(b30)“Organo tin fungicides” (Fungicide Resistance Action Committee (FRAC) code 30) inhibit adenosine triphosphate (ATP) synthase in oxidative phosphorylation pathway. Examples include fentin acetate, fentin chloride and fentin hydroxide.
(b31)“Carboxylic acid fungicides” (Fungicide Resistance Action Committee (FRAC) code 31) inhibit growth of fungi by affecting deoxyribonucleic acid (DNA) topoisomerase type II (gyrase). Examples include oxolinic acid.
(b32)“Heteroaromatic fungicides” (Fungicide Resistance Action Committee (FRAC) code 32) are proposed to affect DNA/ribonucleic acid (RNA) synthesis. Heteroaromatic fungicides include isoxazoles and isothiazolones. The isoxazoles include hymexazole and the isothiazolones include octhilinone.
(b33)“Phosphonate fungicides” (Fungicide Resistance Action Committee (FRAC) code 33) include phosphorous acid and its various salts, including fosetyl-aluminum.
(b34)“Phthalamic acid fungicides” (Fungicide Resistance Action Committee (FRAC) code 34) include teclofthalam.
(b35)“Benzotriazine fungicides” (Fungicide Resistance Action Committee (FRAC) code 35) include triazoxide.
(b36)“Benzene-sulfonamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 36) include flusulfamide.
(b37)“Pyridazinone fungicides” (Fungicide Resistance Action Committee (FRAC) code 37) include diclomezine.
(b38)“Thiophene-carboxamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 38) are proposed to affect ATP production. Examples include silthiofam.
(b39)“Pyrimidinamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 39) inhibit growth of fungi by affecting phospholipid biosynthesis and include diflumetorim.
(b40)“Carboxylic acid amide (CAA) fungicides” (Fungicide Resistance Action Committee (FRAC) code 40) are proposed to inhibit phospholipid biosynthesis and cell wall deposition. Inhibition of these processes prevents growth and leads to death of the target fungus. Carboxylic acid amide fungicides include cinnamic acid amides, valinamide carbamates, carbamates and mandelic acid amides. The cinnamic acid amides include dimethomorph and flumorph. The valinamide carbamates include benthiavalicarb, benthiavalicarb-isopropyl, iprovalicarb, valifenalate and valiphenal. The carbamates include tolprocarb. The mandelic acid amides include mandipropamid, N-[2-[4-[[3-(4- chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(methylsulfonyl)- amino]butanamide and N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]- ethyl]-3-methyl-2-[(ethylsulfonyl)amino]butanamide.
(b41)“Tetracycline antibiotic fungicides” (Fungicide Resistance Action Committee (FRAC) code 41) inhibit growth of fungi by affecting complex 1 nicotinamide adenine dinucleotide (NADH) oxidoreductase. Examples include oxytetracycline.
(b42)“Thiocarbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code 42) include methasulfocarb.
(b43)“Benzamide fungicides” (Fungicide Resistance Action Committee (FRAC) code 43) inhibit growth of fungi by delocalization of spectrin-like proteins. Examples include acylpicolide fungicides such as fluopicolide.
(b44) “Host plant defense induction fungicides” (Fungicide Resistance Action Committee (FRAC) code P) induce host plant defense mechanisms. Host plant defense induction fungicides include benzothiadiazoles, benzisothiazoles and thiadiazolecarboxamides. The benzothiadiazoles include acibenzolar-S-methyl. The benzisothiazoles include probenazole. The thiadiazolecarboxamides include tiadinil and isotianil.
(b45)“Multi-site contact fungicides” inhibit fungal growth through multiple sites of action and have contact/preventive activity. This class of fungicides includes: (b45.1) “copper fungicides” (Fungicide Resistance Action Committee (FRAC) code M1)”, (b45.2) “sulfur fungicides” (Fungicide Resistance Action Committee (FRAC) code M2), (b45.3) “dithiocarbamate fungicides” (Fungicide Resistance Action Committee (FRAC) code M3), (b45.4)“phthalimide fungicides” (Fungicide Resistance Action Committee (FRAC) code M4), (b45.5)“chloronitrile fungicides” (Fungicide Resistance Action Committee (FRAC) code M5), (b45.6)“sulfamide fungicides” (Fungicide Resistance Action Committee (FRAC) code M6), (b45.7)“guanidine fungicides” (Fungicide Resistance Action Committee (FRAC) code M7), (b45.8)“triazine fungicides” (Fungicide Resistance Action Committee (FRAC) code M8) and (b45.9)“quinone fungicides” (Fungicide Resistance Action Committee (FRAC) code M9). “Copper fungicides” are inorganic compounds containing copper, typically in the copper(II) oxidation state; examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). “Sulfur fungicides” are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur. “Dithiocarbamate fungicides” contain a dithiocarbamate molecular moiety; examples include mancozeb, metiram, propineb, ferbam, maneb, thiram, zineb and ziram.“Phthalimide fungicides” contain a phthalimide molecular moiety; examples include folpet, captan and captafol.“Chloronitrile fungicides” contain an aromatic ring substituted with chloro and cyano; examples include chlorothalonil. “Sulfamide fungicides” include dichlofluanid and tolyfluanid. “Guanidine fungicides” include dodine, guazatine, iminoctadine albesilate and iminoctadine triacetate. “Triazine fungicides” include anilazine.“Quinone fungicides” include dithianon.
(b46)“Fungicides other than fungicides of classes (b1) through (b45)” include certain fungicides whose mode of action may be unknown. These include: (b46.1)“thiazole carboxamide fungicides” (Fungicide Resistance Action Committee (FRAC) code U5), (b46.2)“phenylacetamide fungicides” (Fungicide Resistance Action Committee (FRAC) code U6), (b46.3)“arylphenylketone fungicides” (Fungicide Resistance Action Committee (FRAC) code U8) and (b46.4)“triazolopyrimidine fungicides”. The thiazole carboxamides include ethaboxam. The phenylacetamides include cyflufenamid and N- [[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3-difluorophenyl]-methylene]- benzeneacetamide. The arylphenylketones include benzophenones such as metrafenone and benzoylpyridines such as pyriofenone. The triazolopyrimidines include ametoctradin. Class (b46) (i.e.“Fungicides other than classes (b1) through (b45)”) also includes bethoxazin, fluxapyroxad, neo-asozin (ferric methanearsonate), pyrrolnitrin, quinomethionate, tebufloquin, isofetamid, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxy- phenyl]ethyl]-3-methyl-2-[(methylsulfonyl)amino]butanamide, N-[2-[4-[[3-(4-chloro- phenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(ethylsulfonyl)amino]- butanamide, 2-[[2-fluoro-5-(trifluoromethyl)phenyl]thio]-2-[3-(2-methoxyphenyl)-2-thiazo- lidinylidene]acetonitrile, 3-[5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl]pyridine, 4-fluorophenyl N-[1-[[[1-(4-cyanophenyl)ethyl]sulfonyl]methyl]propyl]carbamate, 5-chloro- 6-(2,4,6-trifluorophenyl)-7-(4-methylpiperidin-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine, N-(4- chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide, N-[[(cyclopropylmethoxy)- amino][6-(difluoromethoxy)-2,3-difluorophenyl]methylene]benzeneacetamide, N'-[4-[4- chloro-3-(trifluoromethyl)phenoxy]-2,5-dimethylphenyl]-N-ethyl-N-methylmethanimid- amide, 1-[(2-propenylthio)carbonyl]-2-(1-methylethyl)-4-(2-methylphenyl)-5-amino-1H- pyrazol-3-one, N'-[4-[[3-[(4-chlorophenyl)methyl]-1,2,4-thiadiazol-5-yl]oxy]-2,5-dimethyl- phenyl]-N-ethyl-N-methyl-methanimidamide, 1,1-dimethylethyl N-[6-[[[[(1-methyl-1H- tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate, 3-butyn-1-yl N- [6-[[[[(1-methyl-1H-tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2- pyridinyl]carbamate, 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c']dipyrrole- 1,3,5,7(2H,6H)-tetrone, 5-fluoro-2-[(4-methylphenyl)methoxy]-4-pyrimidinamine, 5-fluoro- 2-[(4-fluorophenyl)methoxy]-4-pyrimidinamine, α-[3-(4-chloro-2-fluorophenyl)-5-(2,4- difluorophenyl)isoxazol-4-yl]pyrid-3-ylmethanol, (αS)-[3-(4-chloro-2-fluorophenyl)-5-(2,4- difluorophenyl)isoxazol-4-yl]pyrid-3-ylmethanol and (αR)-[3-(4-chloro-2-fluorophenyl)-5- (2,4-difluorophenyl)isoxazol-4-yl]pyrid-3-ylmethanol.
Therefore of note is a mixture (i.e. composition) comprising as component (a) a compound of Formula 1 (or an N-oxide or salt thereof) and as component (b) at least one fungicidal compound selected from the group consisting of the aforedescribed classes (b1) through (b46). Also of note are embodiments wherein component (b) comprises at least one fungicide from each of two different groups selected from (b1) through (b46). Also of note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of particular note is a mixture (i.e. composition) comprising a compound of Formula 1 and at least one fungicidal compound selected from the group of specific compounds listed above in connection with classes (b1) through (b46). Also of particular note is a composition comprising said mixture (in fungicidally effective amount) and further comprising at least one additional surfactant selected from the group consisting of surfactants, solid diluents and liquid diluents.
Examples of other biologically active compounds or agents with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, acetamiprid, acrinathrin, amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl, bifenthrin, bifenazate, buprofezin, carbofuran, cartap, chlorantraniliprole, chlorfenapyr, chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide, clothianidin, cyantraniliprole (3-bromo- 1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H- pyrazole-5-carboxamide), cyflumetofen, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda- cyhalothrin, cypermethrin, cyromazine, deltamethrin, diafenthiuron, diazinon, dieldrin, diflubenzuron, dimefluthrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, fenothiocarb, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate, tau-fluvalinate, flufenerim (UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, meperfluthrin, metaflumizone, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methoxyfenozide, metofluthrin, milbemycin oxime, monocrotophos, nicotine, nitenpyram, nithiazine, novaluron, noviflumuron (XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, profluthrin, pymetrozine, pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen (BSN 2060), spirotetramat, sulfoxaflor, sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap- sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon and triflumuron; and biological agents including entomopathogenic bacteria, such as Bacillus thuringiensis subsp. aizawai, Bacillus thuringiensis subsp. kurstaki, and the encapsulated delta-endotoxins of Bacillus thuringiensis (e.g., Cellcap, MPV, MPVII); entomopathogenic fungi, such as green muscardine fungus; and entomopathogenic virus including baculovirus, nucleopolyhedro virus (NPV) such as HzNPV, AfNPV; and granulosis virus (GV) such as CpGV. General references for agricultural protectants (i.e. insecticides, fungicides, nematocides, acaricides, herbicides and biological agents) include The Pesticide Manual, 13th Edition, C. D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2003 and The BioPesticide Manual, 2nd Edition, L. G. Copping, Ed., British Crop Protection Council, Farnham, Surrey, U.K., 2001.
For embodiments where one or more of these various mixing partners are used, the weight ratio of these various mixing partners (in total) to the compound of Formula 1 is typically between about 1:3000 and about 3000:1. Of note are weight ratios between about 1:300 and about 300:1 (for example ratios between about 1:30 and about 30:1). One skilled in the art can easily determine through simple experimentation the biologically effective amounts of active ingredients necessary for the desired spectrum of biological activity. It will be evident that including these additional components may expand the spectrum of diseases controlled beyond the spectrum controlled by the compound of Formula 1 alone.
In certain instances, combinations of a compound of this invention with other biologically active (particularly fungicidal) compounds or agents (i.e. active ingredients) can result in a greater-than-additive (i.e. synergistic) effect. Reducing the quantity of active ingredients released in the environment while ensuring effective pest control is always desirable. When synergism of fungicidal active ingredients occurs at application rates giving agronomically satisfactory levels of fungal control, such combinations can be advantageous for reducing crop production cost and decreasing environmental load.
Compounds of this invention and compositions thereof can be applied to plants genetically transformed to express proteins toxic to invertebrate pests (such as Bacillus thuringiensis delta-endotoxins). The effect of the exogenously applied fungicidal compounds of this invention may be synergistic with the expressed toxin proteins.
Of note is a combination of a compound of Formula 1 with at least one other fungicidal active ingredient. Of particular note is such a combination where the other fungicidal active ingredient has different site of action from the compound of Formula 1. In certain instances, a combination with at least one other fungicidal active ingredient having a similar spectrum of control but a different site of action will be particularly advantageous for resistance management. Thus, a composition of the present invention can further comprise a biologically effective amount of at least one additional fungicidal active ingredient having a similar spectrum of control but a different site of action.
Of particular note are compositions which in addition to a compound of Formula 1 include at least one compound selected from the group consisting of (1) alkylenebis(dithiocarbamate) fungicides; (2) cymoxanil; (3) phenylamide fungicides; (4) proquinazid (6-iodo-3-propyl-2-propyloxy-4(3H)-quinazolinone); (5) chlorothalonil; (6) carboxamides acting at complex II of the fungal mitochondrial respiratory electron transfer site; (7) quinoxyfen; (8) metrafenone; (9) cyflufenamid; (10) cyprodinil; (11) copper compounds; (12) phthalimide fungicides; (13) fosetyl-aluminum; (14) benzimidazole fungicides; (15) cyazofamid; (16) fluazinam; (17) iprovalicarb; (18) propamocarb; (19) validomycin; (20) dichlorophenyl dicarboximide fungicides; (21) zoxamide; (22) fluopicolide; (23) mandipropamid; (24) carboxylic acid amides acting on phospholipid biosynthesis and cell wall deposition; (25) dimethomorph; (26) non-DMI sterol biosynthesis inhibitors; (27) inhibitors of demethylase in sterol biosynthesis; (28) bc1 complex fungicides; and salts of compounds of (1) through (28).
Further descriptions of the above groups of fungicidal compounds are provided below. Alkylenebis(dithiocarbamate)s (group (1)) include compounds such as mancozeb, maneb, propineb and zineb. Phenylamides (group (3)) include compounds such as metalaxyl, benalaxyl, furalaxyl and oxadixyl. Carboxamides (group (6)) include compounds such as boscalid, carboxin, fenfuram, flutolanil, furametpyr, mepronil, oxycarboxin, thifluzamide, penthiopyrad and N-[2-(1,3-dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H- pyrazole-4-carboxamide (PCT Patent Publication WO 2003/010149), and are known to inhibit mitochondrial function by disrupting complex II (succinate dehydrogenase) in the respiratory electron transport chain. Copper compounds (group (11)) include compounds such as copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). Phthalimides (group (12)) include compounds such as folpet and captan. Benzimidazole fungicides (group (14)) include benomyl and carbendazim. Dichlorophenyl dicarboximide fungicides (group (20)) include chlozolinate, dichlozoline, iprodione, isovaledione, myclozolin, procymidone and vinclozolin.
Sterol biosynthesis inhibitors (group (27)) control fungi by inhibiting enzymes in the sterol biosynthesis pathway. Demethylase-inhibiting fungicides have a common site of action within the fungal sterol biosynthesis pathway, involving inhibition of demethylation at position 14 of lanosterol or 24-methylene dihydrolanosterol, which are precursors to sterols in fungi. Compounds acting at this site are often referred to as demethylase inhibitors, DMI fungicides, or DMIs. The demethylase enzyme is sometimes referred to by other names in the biochemical literature, including cytochrome P-450 (14DM). The demethylase enzyme is described in, for example, J. Biol. Chem. 1992, 267, 13175–79 and references cited therein. DMI fungicides are divided between several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. The triazoles include azaconazole, bromuconazole, cyproconazole, difenoconazole, diniconazole (including diniconazole-M), epoxiconazole, etaconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. The imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole, oxpoconazole, prochloraz and triflumizole. The pyrimidines include fenarimol, nuarimol and triarimol. The piperazines include triforine. The pyridines include buthiobate and pyrifenox. Biochemical investigations have shown that all of the above mentioned fungicides are DMI fungicides as described by K. H. Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action, H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.
Non-DMI sterol biosynthesis inhibitors (group (26)) include morpholine and piperidine fungicides. The morpholines and piperidines are sterol biosynthesis inhibitors that have been shown to inhibit steps in the sterol biosynthesis pathway at a point later than the inhibitions achieved by the DMI sterol biosynthesis (group (27)). The morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. The piperidines include fenpropidin.
bc 1 Complex Fungicides (group 28) have a fungicidal mode of action which inhibits the bc 1 complex in the mitochondrial respiration chain. The bc 1 complex is sometimes referred to by other names in the biochemical literature, including complex III of the electron transfer chain, and ubihydroquinone:cytochrome c oxidoreductase. This complex is uniquely identified by Enzyme Commission number EC1.10.2.2. The bc 1 complex is described in, for example, J. Biol. Chem. 1989, 264, 14543-48; Methods Enzymol. 1986, 126, 253–71; and references cited therein. Strobilurin fungicides such as azoxystrobin, dimoxystrobin, enestroburin (SYP-Z071), fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin and trifloxystrobin are known to have this mode of action (H. Sauter et al., Angew. Chem. Int. Ed. 1999, 38, 1328-1349). Other fungicidal compounds that inhibit the bc 1 complex in the mitochondrial respiration chain include famoxadone and fenamidone.
Examples of component (b) fungicides include acibenzolar-S-methyl, aldimorph, ametoctradin, amisulbrom, anilazine, azaconazole, azoxystrobin, benalaxyl, benalaxyl-M, benodanil, benomyl, benthiavalicarb, benthiavalicarb-isopropyl, bethoxazin, binapacryl, biphenyl, bitertanol, bixafen, blasticidin-S, boscalid, bromuconazole, bupirimate, carboxin, carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil, chlozolinate, clotrimazole, copper salts such as Bordeaux mixture (tribasic copper sulfate), copper hydroxide and copper oxychloride, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dichlofluanid, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, diflumetorim, dimethirimol, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinocap, dithianon, dodemorph, dodine, edifenphos, enestroburin, epoxiconazole, ethaboxam, ethirimol, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin acetate, fentin chloride, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluopicolide (also known as picobenzamid), fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil (2-[[2-fluoro-5- (trifluoromethyl)phenyl]thio]-2-[3-(2-methoxyphenyl)-2-thiazolidinylidene]acetonitrile), flutolanil, flutriafol, fluxapyroxad, folpet, fosetyl-aluminum, fuberidazole, furalaxyl, furametpyr, hexaconazole, hymexazol, guazatine, imazalil, imibenconazole, iminoctadine, iodocarb, ipconazole, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, kresoxim-methyl, mancozeb, mandipropamid, maneb, mepronil, meptyldinocap, metalaxyl, metalaxyl-M, metconazole, methasulfocarb, metiram, metominostrobin, mepanipyrim, metrafenone, myclobutanil, naftifine, neo-asozin (ferric methanearsonate), nuarimol, octhilinone, ofurace, orysastrobin, oxadixyl, oxolinic acid, oxpoconazole, oxycarboxin, oxytetracycline, penconazole, pencycuron, penflufen, penthiopyrad, pefurazoate, phosphorous acid and salts, phthalide, picoxystrobin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propamocarb-hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, pyrrolnitrin, quinomethionate, quinoxyfen, quintozene, sedaxane, silthiofam, simeconazole, spiroxamine, streptomycin, sulfur, tebuconazole, tebufloquin, tecloftalam, tecnazene, terbinafine, tetraconazole, thiabendazole, thifluzamide, thiophanate, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph, triflumizole, tricyclazole, trifloxystrobin, triforine, trimorphamide, triticonazole, uniconazole, validamycin, valifenalate (valiphenal), vinclozolin, zineb, ziram, zoxamide, N'-[4-[4-chloro-3-(trifluoromethyl)phenoxy]-2,5- dimethylphenyl]-N-ethyl-N-methylmethanimidamide, 5-chloro-6-(2,4,6-trifluorophenyl)-7- (4-methylpiperidin-1-yl)[1,2,4]triazolo[1,5-a]pyrimidine (BAS600), penflufen (N-[2-(1,3- dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide), N-[2-[4-[[3-(4- chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(methylsulfonyl)- amino]butanamide, N-[2-[4-[[3-(4-chlorophenyl)-2-propyn-1-yl]oxy]-3-methoxyphenyl]- ethyl]-3-methyl-2-[(ethylsulfonyl)amino]butanamide, 2-butoxy-6-iodo-3-propyl-4H-1- benzopyran-4-one, 3-[5-(4-chlorophenyl)-2,3-dimethyl-3-isoxazolidinyl]pyridine, 4- fluorophenyl N-[1-[[[1-(4-cyanophenyl)ethyl]sulfonyl]methyl]propyl]carbamate, N- [[(cyclopropylmethoxy)amino][6-(difluoromethoxy)-2,3-difluorophenyl]methylene]benzene- acetamide, ^-(methoxyimino)-N-methyl-2-[[[1-[3-(trifluoromethyl)phenyl]ethoxy]imino]- methyl]benzeneacetamide, N'-[4-[4-chloro-3-(trifluoromethyl)phenoxy]-2,5-dimethyl- phenyl]-N-ethyl-N-methylmethanimidamide, N-(4-chloro-2-nitrophenyl)-N-ethyl-4-methyl- benzenesulfonamide, 2-[[[[3-(2,6-dichlorophenyl)-1-methyl-2-propen-1-ylidene]amino]- oxy]methyl]- ^-(methoxyimino)-N-methylbenzeneacetamide, 1-[(2-propenylthio)carbonyl]- 2-(1-methylethyl)-4-(2-methylphenyl)-5-amino-1H-pyrazol-3-one, ethyl-6-octyl-[1,2,4]- triazolo[1,5-a]pyrimidin-7-ylamine, pentyl N-[4-[[[[(1-methyl-1H-tetrazol-5-yl)phenyl- methylene]amino]oxy]methyl]-2-thiazolyl]carbamate and pentyl N-[6-[[[[(1-methyl-1H- tetrazol-5-yl)phenylmethylene]amino]oxy]methyl]-2-pyridinyl]carbamate
Of note are combinations of compounds of Formula 1 (or an N-oxide or salt thereof) (i.e. component (a) in compositions) with azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, pyrametostrobin, pyraoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, carbendazim, chlorothalonil, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, bromuconazole, cyproconazole, difenoconazole, epoxiconazole, fenbuconazole, flusilazole, fluxapyroxad, hexaconazole, ipconazole, metconazole, penconazole, propiconazole, proquinazid, prothioconazole, pyriofenone, tebuconazole, triticonazole, famoxadone, prochloraz, penthiopyrad and boscalid (nicobifen) (i.e. as component (b) in compositions).
Preferred for better control of plant diseases caused by fungal plant pathogens (e.g., lower use rate or broader spectrum of plant pathogens controlled) or resistance management are mixtures of a compound of this invention with a fungicide selected from the group: azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin, picoxystrobin, pyrametostrobin, pyraoxystrobin, dimoxystrobin, metominostrobin/fenominostrobin, quinoxyfen, metrafenone, cyflufenamid, fenpropidine, fenpropimorph, cyproconazole, epoxiconazole, flusilazole, metconazole, propiconazole, proquinazid, prothioconazole, pyriofenone, tebuconazole, triticonazole, famoxadone and penthiopyrad.
Table A1 lists specific combinations of a component (b) compound with Compound 1 (Index Table A) as component (a) illustrative of the mixtures, compositions and methods of the present invention. Compound numbers refer to compounds in Index Table A. The second column of Table A1 lists ranges of Typical Weight Ratios the component (b) compound (e.g., acibenzolar-S-methyl in the first line) is applied with Compound 1 as component (a). The third and fourth columns of Table A1 list ranges of weight ratios for rates at which the component (a) compound is More Typically and Most Typically applied to a field-grown crop relative to component (b). The fifth column of Table A1 lists an Illustrative Weight Ratio for rates at which the component (a) compound is typically applied to a field-grown crop relative to component (b). Thus, for example, the first line of Table A1 specifically discloses the combination of acibenzolar-S-methyl with Compound 1 is typically applied in a weight ratio of acibenzolar-S-methyl to Compound 1 of between 2:1 and 1:180 (i.e. component (b):component (a) to component (b):component (a)); more typically applied in a weight ratio of acibenzolar-S-methyl to Compound 1 of between 1:1 and 1:60; most typically applied in a weight ratio of acibenzolar-S-methyl to Compound 1 of between 1:1 and 1:18; and is applied in a weight ratio of acibenzolar-S-methyl to Compound 1 of 1:4. The remaining lines of Table A1 are to be construed similarly.
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Tables A2 through A12 are each constructed the same as Table A1 above except that the entry under the row heading“Component (a)” in Table A1” is replaced with the res ective entries under the row headin “Com onent a” shown below.
Figure imgf000072_0002
The control efficacy of compounds of this invention on specific pathogens is demonstrated in TABLE A below. The pathogen control protection afforded by the compounds is not limited, however, to the species described in Tests A-E below. Descriptions of the compounds are provided in Index Table A below. The following abbreviations are used in the index table:“Cmpd. No.” means compound number and“Ex.” stands for“Example” and is followed by a number indicating in which example the compound is prepared. In Index Table A, the numerical value reported in the column“AP + (M+1)”, is the molecular weight of the observed molecular ion formed by addition of H + (molecular weight of 1) to the molecule having the greatest isotopic abundance (i.e. M); the numerical value reported in the column “AP- (M-1)”, is the molecular weight of the observed molecular ion formed by loss of H + (molecular weight of 1) from the molecule having the greatest isotopic abundance (i.e. M). The presence of molecular ions containing one or more higher atomic weight isotopes of lower abundance (e.g., 37 Cl, 81 Br) is not reported. The reported M+1 and M-1 peaks were observed by mass spectrometry using atmospheric pressure chemical ionization (AP+).
Figure imgf000073_0001
BIOLOGICAL EXAMPLES OF THE INVENTION
General protocol for preparing test suspensions for Tests A-E: the test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at the desired concentration (in ppm) in acetone and purified water (50/50 mix by volume) containing 250 ppm of the surfactant Trem ® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in Tests A-E.
TEST A
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita f. sp. tritici (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20 °C for 24 h, and then moved to a growth chamber at 20 °C for 7 days, after which time visual disease ratings were made. TEST B
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Septoria tritici (the causal agent of wheat leaf blotch) and incubated in a saturated atmosphere at 24 °C for 48 h, and then moved to a growth chamber at 20 °C for 19 days, after which time visual disease ratings were made.
TEST C
The test suspension was sprayed to the point of run-off on tomato seedlings. The following day the seedlings were inoculated with a spore suspension of Botrytis cinerea (the causal agent of tomato Botrytis) and incubated in a saturated atmosphere at 20 °C for 48 h, and then moved to a growth chamber at 24 °C for 3 days, after which time visual disease ratings were made.
TEST D
The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Blumeria graminis f. sp. tritici, (also known as Erysiphe graminis f. sp. tritici, the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20 °C for 8 days, after which time visual disease ratings were made.
TEST E
The test solution was sprayed to the point of run-off on soybean seedlings. The following day the seedlings were inoculated with a spore suspension of Phakopsora pachyrhizi (the causal agent of Asian soybean rust) and incubated in a saturated atmosphere at 22 °C for 24 h and then moved to a growth chamber at 22 °C for 8 days, after which time visual disease ratings were made.
Results for Tests A-E are given in Table A below. In Table A, a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls). A dash (–) indicates no test results.
Figure imgf000074_0001
Figure imgf000075_0001

Claims

CLAIMS What is claimed is:
1. A compound selected from Formula 1, N-oxides and salts thereof,
Figure imgf000076_0001
wherein
R1 is halogen;
R2 is H or halogen;
R3 is halogen;
R4 is H or halogen;
X is NR 5 or CR 6 OR 7 ;
R5 is H, amino, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -CH(=O),
-SO - 3 M+, -S(=O)mR8, -C(=W)R9 or OR10; or C1-C6 alkyl or C1-C6 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R11 ;
R6 is H or C 1 -C 6 alkyl;
R7 is H, amino, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -CH(=O),
-SO - 3 M+, -S(=O) m R8 or -C(=W)R9; or C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 ; R8 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
R9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 3 -C 6
dialkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy C 2 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl; R10 is H, -CH(=O), C3-C6 cycloalkyl, -SO –
3 M + or -C(=W)R 12 ; or C1-C6 alkyl or C1 -C 6 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 13 ;
each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl; R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 3 -C 6
dialkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl; each R13 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl;
W is O or S;
M+ is K, Na or Li; and
m is 0, 1 or 2.
2. A compound of Claim 1 wherein:
R1 is Br, Cl or F;
R2 is halogen;
R3 is Br, Cl or F;
R4 is H, Br, Cl or F;
R5 is H, C 2 -C 3 alkenyl, C 3 -C 4 alkynyl, cyclopropyl, -CH(=O),
-S(=O) m R8, -C(=W)R9 or OR10; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 ; R 6 is H or methyl;
R7 is H, -CH(=O) or -C(=W)R9; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 2 substituents independently selected from R 11 ;
R8 is methyl or halomethyl;
R9 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl;
R10 is H, -CH(=O), C 3 -C 6 cycloalkyl or -C(=W)R12; or C 1 -C 3 alkyl or C 1 -C 3
haloalkyl, each optionally substituted with up to 1 substituent selected from R 13 ; each R11 is independently cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio;
R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 2 -C 6 alkylaminoalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl;
R13 is cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C 1 -C 6 alkylthio; and
W is O.
3. A compound of Claim 2 wherein
R2 is Br, Cl or F;
R5 is H, cyclopropyl, -CH(=O), -C(=W)R9 or OR10; or C1-C3 alkyl or C1-C3
haloalkyl, each optionally substituted with up to 1 substituent selected from R 11 ; R7 is H, -CH(=O) or -C(=W)R9; or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, each optionally substituted with up to 1 substituent selected from R 11 ;
R9 is C 1 -C 3 alkyl, C 2 -C 4 alkoxyalkyl, C 4 -C 6 cycloalkylalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4 alkenyloxy C 1 -C 3 alkylthio or C 2 -C 4 alkylthioalkyl;
R10 is H, -CH(=O), cyclopropyl, -C(=W)R12, C1-C3 alkyl or C1-C3 haloalkyl;
R11 is cyano, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy or C 1 -C 3 alkylthio; and
R12 is C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, C 4 -C 8 cycloalkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 1 -C 6 alkylthio or C 2 -C 6 alkylthioalkyl.
4. A compound of Claim 3 wherein
R5 is H, -CH(=O), -C(=W)R9, OR10, C1-C3 alkyl or C1-C3 haloalkyl;
R6 is H;
R7 is H, -CH(=O), -C(=W)R9, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
R9 is C 1 -C 3 alkyl, C 2 -C 3 alkoxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 2 -C 4
alkenyloxy or C 1 -C 3 alkylthio; and
R10 is cyclopropyl, methyl or ethyl.
5. A compound of Claim 4 wherein
R1 is Br or Cl;
R2 is Cl or F;
R4 is H or F;
R5 is H, -CH(=O), methyl or methoxy;
R7 is H, -CH(=O), -C(=W)R 9 , methyl or halomethyl; and
R9 is methyl, ethyl, methoxy, ethoxy, methylthio or ethylthio.
6. A compound of Claim 5 wherein
X is NH;
R1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is H; or
R1 is Br or Cl, R 2 is F, R 3 is Br, Cl or F and R 4 is F; or
R1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is H; or
R1 is Br or Cl, R 2 is Cl, R 3 is Br, Cl or F and R 4 is F.
7. A compound of Claim 1 which is selected from the group:
4-[5-[(2,6-dichloro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3,5- difluorobenzonitrile;
4-[5-[(2,6-dichloro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3- fluorobenzonitrile; 4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3,5- difluorobenzonitrile;
4-[5-[(2-chloro-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3,5- difluorobenzonitrile; and
4-[5-[(2-bromo-6-fluoro-4-methylphenyl)amino]-1,3-dimethyl-1H-pyrazol-4-yl]-3- chlorobenzonitrile.
8. A fungicidal composition comprising (a) a compound of Claim 1; and (b) at least one other fungicide.
9. A fungicidal composition comprising (a) a compound of Claim 1; and (b) at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents.
10. A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed, a fungicidally effective amount of a compound of Claim 1.
PCT/US2017/050919 2016-09-16 2017-09-11 Fungicidal pyrazoles WO2018052838A1 (en)

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* Cited by examiner, † Cited by third party
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CN110591675A (en) * 2019-10-14 2019-12-20 中国石油化工股份有限公司 Profile control and viscosity reduction integrated foaming agent for heavy oil reservoir and preparation method thereof
WO2020051402A1 (en) 2018-09-06 2020-03-12 Fmc Corporation Fungicidal nitroanilino substituted pyrazoles
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CN112969688B (en) * 2018-09-06 2024-06-04 Fmc公司 Fungicidal nitroaniline-substituted pyrazoles
EP4388876A2 (en) 2018-09-06 2024-06-26 FMC Corporation Fungicidal nitroanilino substituted pyrazoles
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